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INTRODUCTION Intravenous prostacyclin-analogs (PCA, e.g. epoprostenol, treprostinil, iloprost) have become an essential part in the therapy of patients with pulmonary hypertension (PH), mainly pulmonary arterial hypertension (PAH). They show considerable differences in pharmacology. A combination therapy including intravenous drugs is regarded as the "gold standard" in most of PAH patients. AREAS COVERED This review discusses and summarizes the studies and concepts on which this therapy is based. To date, intravenous prostacyclin-analogs are mainly administered when standard therapy fails to improve patients to low-risk status. However, preliminary data from uncontrolled studies suggest that an "upfront triple" therapy including intravenous or subcutaneous prostacyclin-analogs could be preferable in selected patients. EXPERT OPINION Various IV PCA have been evaluated in the treatment of patients with PAH. Today, combination therapy is the "gold standard" for the majority of patients. Intravenous PCA is recommended from functional class III onwards. Timing of its initiation is still a point of discussion. An escalation of therapy to IV or SC PCA is always necessary if a low-risk status cannot be achieved with other targeted therapies. Preliminary data suggest that selected patients could benefit from an "upfront triple" therapy. Controlled studies on which such recommendation could be based are lacking.

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.

Objectives We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis. Methods This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year ( Results Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35–68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline. Conclusion Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year. ClinicalTrials.gov identifier NCT02663895.

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 9 bps (17.5 months) compared to doses ≤9 bps (9.5 moths; P 9 bps at years 1, 2, and 3 ( P 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.

Subcutaneous insulin resistance syndrome is a rare condition that causes difficulty in glycemic control due to severe resistance to subcutaneous insulin injections. We herein present a case of a 40-year-old woman with type 2 diabetes mellitus who had been diagnosed with subcutaneous insulin resistance syndrome since the age of 29 years, and had been persistently treated with continuous subcutaneous insulin infusion using a mixture of insulin lispro and heparin. The patient was switched from insulin lispro plus heparin to ultra-rapid insulin lispro; given that it contains treprostinil and citrate, it is expected to have similar effects as heparin, and shows similar glucose-lowering effects and insulin absorption. Our results suggest that treatment with ultra-rapid insulin lispro is effective for subcutaneous insulin resistance syndrome.

While parenteral prostacyclin (pPCY) therapy, delivered either subcutaneously or intravenously, is recommended for pulmonary arterial hypertension patients with severe or rapidly developing disease, some patients refuse this treatment. This study aimed to understand, directly from patients with pulmonary arterial hypertension, why pPCY was refused and, in some cases, later accepted. Interviews were conducted with 25 pulmonary arterial hypertension patients who previously refused pPCY therapy (Group A: Refused/Never initiated (n = 9) and Group B: Refused/Initiated (n = 16)). Patients in both groups believed that pPCY could improve their symptoms, slow disease progression, and provide them a greater ability to perform activities. Reasons for refusal included concern over side effects and the perceived limitations of pPCY on daily activities. Group A perceived their decision as a balance between quality of life and prolonging life and most acknowledged they would reconsider pPCY if other treatment options were exhausted. Group B cited they initiated therapy due to a worsening of symptoms, disease progression, to improve quality of life, to be there for their family, or a desire to live. Following initiation, Group B indicated their experience met expectations with reduced symptoms, slowed disease progression, and perception of improved survival; concerns related to pPCY were described as manageable. Given the efficacy of pPCY therapy, clinicians should apply knowledge of these findings in clinical practice. Patients noted improvements to parenteral pump technologies to include smaller size, water resistance, and implantability may increase their acceptance of this modality. Development efforts should focus on technologies that increase the acceptance of pPCY when indicated.

Aims Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary arterial pressure, resulting in right ventricular overload, right heart failure and eventually death. Treprostinil is a prostacyclin analogue that is used in the treatment of PAH. As an orphan drug, limited information is available regarding its disposition and its use in special populations such as elderly, paediatric and pregnant patients. The objective of the current study was to develop a robust physiologically based pharmacokinetic (PBPK) model for treprostinil intravenous injection and extended-release tablet as the first step to optimize treprostinil pharmacotherapy in patients. Methods PBPK model was built using Simcyp simulator which integrated physicochemical properties, observed or predicted parameters for drug absorption, distribution and elimination for treprostinil, and population specific physiological characteristics. Three clinical trials after intravenous infusion and nine studies after oral administration of treprostinil extended-release tablet in healthy volunteers were used to develop and validate the model. The simulated PK profiles were compared with the observed data. Extrapolation of the model to patient populations including patients with hepatic impairment was conducted to validate the predictions. Results Most of the observed data were within the 5th and 95th percentile interval of the prediction. Most of the percentage error in the PK parameters were within ±50% of the corresponding observed parameters. The developed model predicted the lung exposure of treprostinil to be approximately 0.17 times of concentration in plasma. Conclusion Predicted absorption, distribution, and metabolic enzyme kinetics gave an insight into the disposition of treprostinil in humans. Extrapolation of the established model to patient populations with hepatic impairment successfully documented the model reliability. The developed model has the potential to be used in the PK predictions in other special patient populations with different demographic, physiological and pathological characteristics.

Purpose of review Treatment options for Group 3 pulmonary hypertension, characterized as secondary to chronic hypoxia or lung disease, remain an elusive holy grail for physicians and patients alike. Despite increasing identification and investigation into this pulmonary vasculopathy group with the second-highest frequency and highest mortality, there are no therapeutic interventions that offer the significant improvements in morbidity and mortality comparable to those benefiting other pulmonary hypertension groups including pulmonary arterial hypertension. This review examines the data on available and emerging Group 3 pulmonary hypertension treatments. Recent findings Pulmonary vasodilators have yielded equivocal results in this patient population, although recent evidence shows modestly improved outcomes with inhaled treprostinil in interstitial lung disease-associated pulmonary hypertension. With pulmonary vasodilators providing limited benefit, emerging data support the right ventricle as a potential treatment target in Group 3 pulmonary hypertension. Summary Group 3 pulmonary hypertension is associated with significant morbidity and mortality. Pulmonary vasodilators offer only limited haemodynamic and exertional benefits, and lung transplantation remains the only cure for this deadly disease. The right ventricle may provide a novel intervention target.

There is limited published experience with transitioning pediatric patients from parenteral treprostinil to oral selexipag therapy. In addition, published transitions have typically been protracted, taking several weeks to complete. We present a case series of 3 adolescent patients who were transitioned from parenteral treprostinil to oral selexipag over a 5- to 7-day period. Their clinical courses leading up to the transitions are summarized and their outcomes are described. The 3 patients were successfully rapidly transitioned during an inpatient hospitalization without any observed adverse events or prostacyclin-related side effects. We conclude that when indicated rapid transition of parenteral to oral prostacyclin therapy may be performed safely in adolescents in an inpatient setting.

Pulmonary arterial hypertension (PAH) is a severe disease with poor prognosis and shortened life expectancy. Treatment has traditionally involved the sequential use of endothelin receptor agonists, prostacyclin therapies, and nitric oxide pathway modulators, which each have distinct mechanisms of action leading to pulmonary vasodilation, and improvement in exercise capacity, hemodynamic measures, and clinical outcomes for patients with PAH. This article provides a review of goals of therapy in PAH, determinants of prognosis and levels of patient risk, and additional factors that guide treatment decision making. Recent research in combination therapies has created a paradigm shift in the treatment of PAH and will be reviewed. Additionally, recent updates to the American College of Chest Physicians guidelines will be reviewed along with the updated evidence-based treatment algorithm. Finally, trial data will be evaluated for the recently developed agent selexipag and improved treprostinil delivery formulations that may provide enhanced convenience.

No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear.We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening.A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea.In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).

Background:Systemic venous hypertension and low cardiac output are believed to be important mediators of liver injury after the Fontan procedure. Pulmonary vasodilators have the potential to improve such haemodynamics. The aim of this study was to assess the acute effects of exercise on liver stiffness and venous pressures and to assess the impact of inhaled Treprostinil on this response.Methods:In this prospective, double-blind, placebo-controlled, crossover trial, 14 patients with a Fontan circulation were randomised to inhalation of placebo and Treprostinil. Incremental and constant work rate exercise tests were performed to assess the effect of Treprostinil on exercise tolerance. Venous pressures were measured throughout and liver stiffness at rest and immediately after peak exercise.Results:Mean age was 27.8 ± 7.9 years and 66% were females. Exercise acutely increased liver stiffness by 30% (mean shear wave speed: 2.38 ± 0.71 versus 2.89 ± 0.51 ms, p = 0.02). Peripheral venous pressures increased acutely during both incremental (12.1 ± 2.4 versus 22.6 ± 8.0 mmHg, p < 0.001) and constant work rate exercise (12.5 ± 2.5 versus 23.4 ± 5.2 mmHg, p < 0.001). Overall, Treprostinil failed to attenuate exercise-induced increases in liver stiffness. Compared with placebo, Treprostinil did not significantly impact venous pressure responses, VO2peak, nor exercise endurance times.Conclusions:Peripheral venous pressure increased acutely during exercise by an average of 88% above baseline and was not altered by administration of inhaled Treprostinil. Liver stiffness measured immediately post-exercise increased acutely by an average of 30%, with no attenuation following Treprostinil inhalation.

Objective To investigate the effect of treprostinil on the early postoperative prognosis of patients with severe left heart valvular disease combined with severe pulmonary hypertension (PAH). Methods A retrospective study including 55 patients with severe left heart valvular disease combined with severe PAH who underwent left heart valve replacement in our hospital between January 2019 and May 2019 was conducted. Patients were divided into two groups (treprostinil group and control group), and the clinical data of patients in the two groups were compared and analyzed. Results Compared with the preoperative status, the mean postoperative pulmonary artery pressure (mPAP) in both groups was significantly lower. Compared with the control group, the treprostinil group had a significantly lower mPAP. Moreover, the postoperative mechanical ventilation time, intensive care unit (ICU) stay, and hospital stay of the treprostinil group were significantly shorter than those of the control group. There were no serious drug-related side effects in either group. Conclusions Treprostinil can improve the early postoperative prognosis of patients with severe left heart valvular disease combined with severe PAH undergoing prosthetic valve replacement.

Pulmonary arterial hypertension is a chronic, progressive, and life-threatening disease in children with diverse causes of pulmonary arterial hypertension. The most severe cases of pulmonary arterial hypertension require aggressive treatments with systemic administration of continuous prostacyclin therapy, including treprostinil and epoprostenol. The successful use of continuous subcutaneous treprostinil therapy eliminates the need for an indwelling central venous catheter and its associated risks. However, pain at the subcutaneous infusion site, an expected side effect of this therapy, is often a deterrent to its widespread use. Effective subcutaneous treprostinil site maintenance and pain management is essential to achieve success with this therapy, but strategies surrounding site maintenance and pain control vary significantly between pediatric pulmonary hypertension treatment centers. In an attempt to standardize practice, a survey on the use of subcutaneous treprostinil and site maintenance and pain management strategies, as well as its perceived effectiveness, was disseminated to 13 pediatric pulmonary hypertension centers of the Pediatric Pulmonary Hypertension Network. Responses to the survey were collected and analyzed and were developed into a set of formalized strategies to facilitate knowledge sharing and standardization of practice.

Limited data are available on the transition from subcutaneous to intravenous prostacyclin in precapillary pulmonary hypertension. We performed a retrospective analysis of all patients who were switched from subcutaneous to intravenous treprostinil with an implantable infusion pump. We included 85 consecutive, clinically stable patients (mean age 66 years and range 16-85), who had been treated with subcutaneous treprostinil for mean 9 months (range 1-78) before pump implantation. An interdisciplinary expert panel defined standards for this procedure before the first implantation. As the first patient experienced a significant hypotensive episode indicating treprostinil overdose postoperatively, the time span to stop subcutaneous treprostinil was reduced to 60 minutes for all following patients. No events associated with the switch from subcutaneous to intravenous treprostinil were observed during postoperative hospital stay in 84 (98.8%) patients. Taking into account a likely depot effect of subcutaneous treprostinil patients can safely be switched to the intravenous route by the implantation of an infusion pump.

Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved in TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS). Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously. In guinea pigs, cough with inhaled TRE (1.23 µg·kg−1) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg−1) to induce cough. TRE cough was blocked with IP and tachykinin NK1 receptor antagonists but not with EP1, EP2, EP3, DP1 or bradykinin B2 antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnoea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects. The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibres in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves., Cough induced by inhaled treprostinil and treprostinil palmitil involves the activation of prostacyclin (IP) receptors located on airway tachykinin nerves https://bit.ly/37sXz1I

Pulmonary hypertension (PH) due to interstitial lung disease (ILD; PH-ILD) can complicate a multitude of ILDs, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and nonspecific interstitial pneumonia. Development of PH-ILD is associated with increased need for supplemental oxygen, reduced mobility, and decreased survival. A high index of suspicion is required to make the diagnosis, given the substantial overlap in symptoms with those of ILD without PH. Severely reduced diffusing capacity or 6-min walk test distance, prominent exertional desaturation, and impaired heart rate recovery after exercise are all suggestive of the development of PH-ILD. Traditional transthoracic echocardiography is the most commonly used screening test for PH-ILD, but it lacks sensitivity and specificity. Newer echocardiographic tools involving 3-dimensional assessment of the right ventricle may have a role in both prognosis and the monitoring of patients with PH-ILD. Right-sided heart catheterization remains the gold standard for confirming a diagnosis of PH-ILD. Although there is little debate about the use of supplemental oxygen and diuretic therapy in the treatment of PH-ILD, treatment with pulmonary vasodilator therapy remains controversial. Although several studies have been terminated prematurely for harm, the recently completed INCREASE trial of inhaled treprostinil appears to validate the concept of treating PH-ILD with pulmonary vasodilators and, we hope, will serve as a foundation from which future studies can be developed.

A dry-powder inhaled formulation of treprostinil (LIQ861) produced using PRINT® technology offers a substantial advantage over current nebulized therapy. Treprostinil is a synthetic prostacyclin analogue that is currently approved for inhalation administration to patients with pulmonary arterial hypertension via nebulized Tyvaso® inhalation solution. LTI-101 was a phase 1, placebo-controlled, double-blind, randomized, single-center study that evaluated the ascending single-dose pharmacokinetics of LIQ861 in healthy subjects. Six sequential, escalating doses (25, 50, 75, 100, 125, and 150 mcg) were studied to investigate treprostinil exposure from LIQ861 inhalation. Subjects ( n = 57) were randomly assigned in a 3:1 ratio to receive a single dose of either LIQ861 ( n = 43) or placebo ( n = 14); 56 subjects completed all protocol-defined assessments. Following single-dose administration, treprostinil exposure from LIQ861 increased proportionally across the dose range studied, and the pharmacokinetics profile of treprostinil administered as LIQ861 was similar to prior reports of inhaled treprostinil. All doses of LIQ861 were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities. The most frequently reported treatment-emergent adverse events related to study drug administration were coughing and throat irritation, which are common to dry-powder formulations. Treatment-related treatment-emergent adverse events were reported more frequently at higher dose levels; however, all were assessed as mild in severity. We conclude that the pharmacokinetics profile of treprostinil using a dry-powder inhaled formulation increased in proportion to dose as anticipated and was similar to earlier reports of inhaled, nebulized treprostinil (Tyvaso®). Based on these results, a phase 3 study (INSPIRE; Clinicaltrials.gov Identifier NCT03399604) evaluating the long-term safety and tolerability of LIQ861 in patients with pulmonary arterial hypertension was initiated.

While the prognosis of idiopathic pulmonary arterial hypertension has improved significantly due to newer medications, lung transplantation remains a critical therapeutic option for severe pulmonary arterial hypertension. Hence, it is essential for patients awaiting lung transplantation to avoid complications, including thrombocytopenia, which may affect their surgical outcomes. Herein we present the case of a 21-year-old woman diagnosed with idiopathic pulmonary arterial hypertension at the age of 15. She developed thrombocytopenia while awaiting lung transplantation. Her medication was switched from epoprostenol to treprostinil, suspecting possible drug-induced thrombocytopenia. Furthermore, she was administered thrombopoietin receptor agonists in view of the possibility of idiopathic thrombocytopenic purpura, along with maximum support for right heart failure. Subsequently, her platelet count increased to >70,000/µL, enabling her to successfully undergo bilateral lung transplantation. Post-bilateral lung transplantation, pulmonary arterial hypertension as well as thrombocytopenia appeared to have resolved. In this case, we suspected that thrombocytopenia could have resulted owing to a combination of pulmonary arterial hypertension, right heart failure, drug interactions, and idiopathic thrombocytopenic purpura. Thrombocytopenia is a very critical condition in patients with pulmonary arterial hypertension, especially those awaiting lung transplantation. Several approaches are known to improve intractable thrombocytopenia in patients with pulmonary arterial hypertension.

Purpose of review The present review provides an update on treatment of chronic thromboembolic pulmonary hypertension (CTEPH), a rare form of pulmonary hypertension characterized by precapillary pulmonary hemodynamic parameters with chronic thrombotic occlusion of the pulmonary vasculature. Recent findings Pulmonary thromboendarectomy (PTE) remains the recommended treatment for patients with surgically accessible disease. Recent data suggest that patients preoperatively bridged with medical therapy may have improved outcomes but further research is needed. Riociguat improves hemodynamics, right ventricular function, quality of life, and functional capacity and is the drug of choice for patients with inoperable/persistent disease. Recently published data suggest that endothelin receptor blockers and treprostinil may also have a role in medical management of this patient population. A growing body of evidence indicates that in experienced centers balloon pulmonary angioplasty (BPA) may be a well tolerated and effective adjunct to pharmacological treatment for patients with inoperable disease affecting subsegmental vasculature. Summary Untreated CTEPH carries significant morbidity and mortality. Recent publications provide a wealth of data on safety and efficacy of BPA for inoperable subsegmental disease, but its precise fit in the treatment algorithm, both pharmacological and procedural, requires further investigation. PTE remains the procedure of choice for surgically accessible disease.

Background Add-on therapy with prostacyclin in pediatric refractory pulmonary hypertension (PH) poses a challenge, especially when considering continuous intravenous administration in younger children. A search for alternate routes of drug delivery has led to the clinical investigation of stable and long-acting prostacyclin analogues, such as subcutaneous treprostinil. We reported 2 pediatric cases of PH treated with subcutaneous treprostinil and reviewed the literature on treprostinil use in children. Method The literature review used 3 electronic databases and a combination of terms (treprostinil, pediatric, PH, prostanoid, etc). We also searched for pediatric clinical trials on treprostinil registered on international clinical trial registries. Results The reported cases highlighted the multifactorial nature of PH in pediatrics: a female child with a giant omphalocele, and intracardiac and extracardiac shunts; and a male premature child with a congenital diaphragmatic hernia and long-term PH. The literature review identified 19 studies reporting treprostinil use in 421 children with various types of PH (groups 1 and 3). Subcutaneous treprostinil was the most administered formulation, at a mean dose of 40 ng/kg/min. Overall, 12 clinical trials on treprostinil for children with PH were registered on the clinical trial registries. Most authors concluded that subcutaneous treprostinil was effective, well tolerated, and represented an alternative to intravenous epoprostenol. Conclusions Subcutaneous treprostinil may be a useful adjunct in the therapeutic algorithm for children with severe PH, refractory to oral drugs, and after a complete check-up for all PH etiologies.

This study investigated the efficacy and safety of intravenous treprostinil during the perioperative period in infants with non-restrictive ventricular septal defect (VSD) and severe pulmonary arterial hypertension (PAH) undergoing surgical VSD repair. This was a retrospective study. There were 79 infants with non-restrictive VSD and severe PAH receiving surgical treatment from January to December 2019 in our cardiac center. The patients were divided into the treprostinil group and control group according to whether intravenous treprostinil was used during the perioperative period. There were no significant differences in the preoperative characteristics, including age, sex, weight, ventricular size, or preoperative pulmonary artery pressure, between the two groups. Although the pulmonary artery pressure in both groups was significantly lower postoperatively than preoperatively, the postoperative pulmonary artery systolic pressure was significantly lower in group T than in group C. The postoperative mechanical ventilation time, ICU stay, and hospital stay in group T were shorter than those in group C. Treprostinil can be used effectively and safely to reduce the perioperative pulmonary artery pressure in infants with non-restrictive VSD and severe PAH undergoing surgical VSD repair.

Clinicians may transition patients on parenteral or inhaled prostacyclins to oral treprostinil for ease of use or to avoid adverse effects related to parenteral therapy. However, few data are available to guide these transitions in inpatients. The purpose of this analysis is to describe the inpatient initiation of oral treprostinil at an academic medical system. This is a retrospective cohort analysis of patients newly initiated on oral treprostinil at Cleveland Clinic Heath System from 2015 to 2017. Demographic information regarding pulmonary arterial hypertension (PAH) history and previous PAH therapies were recorded. Outcomes evaluated included doses of oral treprostinil utilized, adverse effects related to therapy, and measures of clinical and functional status before and after the initiation of oral treprostinil. Overall, 29 patients were prescribed oral treprostinil, of which 15 patients were included in the analysis. Common reasons for initiation of oral treprostinil included disease progression (6, 40%) and patient desire (4, 25%). The median duration of transition/initiation of oral treprostinil was 4 days (range, 3–11 days). Median daily dose of oral treprostinil on day 1 of initiation was 2 mg (0.25–4 mg). By day 7, median daily dose was 15 mg (0.75–27.75 mg). Common adverse effects related to therapy were gastrointestinal (7, 47%) and headache (4, 27%). No patients required discontinuation of oral treprostinil due to adverse effects within 90 days of initiation. Inpatient initiation/transition to oral treprostinil was relatively well tolerated. Future studies should evaluate clinical outcomes surrounding the transitioning to oral treprostinil.

Rationale: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin I2 analogs (beraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of DP1 (D prostanoid receptor subtype 1).Objectives: To study the role of DP1 in the progression of PAH and its underlying mechanism.Methods: DP1 levels were examined in pulmonary arteries of patients and animals with PAH. Multiple genetic and pharmacologic approaches were used to investigate DP1-mediated signaling in PAH.Measurements and Main Results: DP1 expression was downregulated in hypoxia-treated pulmonary artery smooth muscle cells and in pulmonary arteries from rodent PAH models and patients with idiopathic PAH. DP1 deletion exacerbated pulmonary artery remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of the DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted pulmonary artery smooth muscle cell hypertrophy and proliferation in response to hypoxia via induction of mTORC1 (mammalian target of rapamycin complex 1) activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-knockout mice. DP1 activation facilitated raptor dissociation from mTORC1 and suppressed mTORC1 activity through PKA (protein kinase A)-dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting the DP1 receptor.Conclusions: DP1 activation attenuates hypoxia-induced pulmonary artery remodeling and PAH through PKA-mediated dissociation of raptor from mTORC1. These results suggest that the DP1 receptor may serve as a therapeutic target for the management of PAH.

Purpose To evaluate the physical and chemical compatibilities of treprostinil sodium and dopamine hydrochloride. Methods Treprostinil sodium (4,000, 76,000, and 500,000 ng/mL) were mixed with dopamine hydrochloride (0.6, 3.2, 6, and 40 mg/mL). Samples were obtained at hours 0, 1, 2, and 4 for physical compatibility and chemical stability testing. Physical compatibility was assessed by visual examination and measurements of turbidity and pH. Drug concentrations were assessed using stability-indicating liquid chromatography mass spectrophotometry (LCMS) for treprostinil sodium and stability-indicating high-performance liquid chromatography (HPLC) for dopamine hydrochloride. Results Treprostinil sodium 4,000 and 76,000 ng/mL, when mixed with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL, were stable for 4 hours. Treprostinil sodium 500,000 ng/mL was stable when mixed with dopamine hydrochloride 0.6 mg/mL for 4 hours, but when mixed with dopamine hydrochloride 3.2, 6, and 40 mg/mL, significant precipitation was seen. Conclusion Treprostinil sodium 4,000 and 76,000 ng/mL were stable for 4 hours during simulated Y-site coadministration with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL. Treprostinil sodium 500,000 ng/mL is stable when mixed with dopamine hydrochloride 0.6 mg/mL.

Parenteral prostanoids are effective for improving outcomes in patients with pulmonary arterial hypertension. However, subcutaneous or intravenous delivery via an external pump places a significant burden on patients. Consequently, the Implantable System for Remodulin© (treprostinil) was developed and is associated with a low rate of complications (United Therapeutics (Research Triangle Park, NC) in collaboration with Medtronic, Inc. (Mounds View, MN)). The current real-world experience study evaluated pulmonary arterial hypertension patients' perceptions of their quality of life, ability to perform activities of daily living, perceptions on the benefits and risks of the implantable system, and their social interactions before and after receiving the implantable system. Pulmonary arterial hypertension patients who had been transitioned from an external infusion pump to the implantable system completed a mix of quantitative and qualitative questions administered online over the course of a six-day period. A total of 20 patients completed the study. All patients reported that their quality of life, confidence out in public, and ability to travel long distances had improved. Over 90% of patients reported that their overall level of independence was better since receiving the implantable system, and most patients indicated that their ability to independently perform specific activities of daily living had improved. Responses to the qualitative questions suggested that the implantable system saved time, improved interpersonal relationships, and increased freedom. Results from this real-world patient experience study suggest this novel delivery system provides improvements in factors that are of substantial importance to patients.

Background Given the improved convenience of oral prostacyclins, there is a shift toward their use in treating pulmonary arterial hypertension (PAH). Objectives Our objective was to compare patient characteristics, medication adherence, healthcare resource use (HCRU), and costs among patients receiving oral treprostinil or selexipag. Methods We used Truven Health MarketScan Commercial and Medicare databases to identify patients with PAH with a diagnosis code for pulmonary hypertension (PH) plus a prescription for oral treprostinil or selexipag from July 2013 to September 2017. Medication adherence, persistence, and all-cause and PAH-related HCRU and costs were compared between cohorts during the 6-month follow-up. Adjusted healthcare costs were obtained using recycled predictions and bootstrapped samples. Results A total of 256 (130 oral treprostinil, 126 selexipag) patients fulfilled the study criteria. The oral treprostinil cohort was more likely to be male, to have previously used parenteral prostacyclins, and to have higher outpatient costs at baseline than the selexipag cohort. During follow-up, both cohorts had similar proportions of patients who were adherent to and persistent with their respective therapies. All-cause and PAH-related medical utilization was generally similar between cohorts. The oral treprostinil cohort had 66.9% lower total PAH-related healthcare costs (mean difference − $75,183; 95% confidence interval [CI] − 102,584 to − 49,771) and 70.6% lower PAH-related pharmacy costs (mean difference − $76,439; 95% CI − 104,512 to − 51,458) than the selexipag cohort, with similar differences in all-cause healthcare and pharmacy costs. Conclusions Lower all-cause and PAH-related total healthcare and pharmacy costs were observed in patients receiving oral treprostinil compared with those receiving selexipag. It will be important to study longer-term costs and clinical outcomes.

Resumen En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.

BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p

Rationale The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute-walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. Objectives This post hoc analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Methods Patients enrolled in INCREASE were analyzed for disease progression events, defined as at least 15% decline in 6-minute-walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, at least 10% decline in forced vital capacity, or death during the duration of the 16-week study. Measurements and Main Results In total, 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared with 215 events (109/163 patients, 67%) in the placebo group (P = 0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute-walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), FVC decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events), and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared with those receiving the placebo (35 vs. 58, 22% vs. 36%; P = 0.005). Conclusions Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared with patients receiving placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice.

Background It remains unknown whether the cutaneous microvascular responses are different between patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and SSc without pulmonary hypertension (PH). Methods We included 59 patients with SSc between March 2013 and September 2019. We divided patients into 4 groups: (a) no PH by right heart catheterization (RHC) (n = 8), (b) no PH by noninvasive screening tests (n = 16), (c) treatment naive PAH (n = 16), and (d) PAH under treatment (n = 19). Microvascular studies using laser Doppler flowmetry (LDF) were done immediately after RHC or at the time of an outpatient clinic visit (group b). Results The median (IQR) age was 59 (54-68) years, and 90% were females. The responses to local thermal stimulation and postocclusive reactive hyperemia, acetylcholine, and sodium nitroprusside iontophoresis were similar among groups. The microvascular response to treprostinil was more pronounced in SSc patients without PH by screening tests (% change: 340 (214-781)) compared with SSc-PAH (naive + treatment) (Perfusion Units (PU) % change: 153 (94-255) % [p = .01]). The response to A-350619 (a soluble guanylate cyclase (sGC) activator) was significantly higher in patients with SSc without PH by screening tests (PU % change: 168 (46-1,296)) than those with SSc-PAH (PU % change: 22 (15-57) % [p = .006]). The % change in PU with A350619 was directly associated with cardiac index and stroke volume index (R: 0.36, p = .03 and 0.39, p = .02, respectively). Conclusions Patients with SSc-PAH have a lower cutaneous microvascular response to a prostacyclin analog treprostinil and the sGC activator A-350619 when compared with patients with SSc and no evidence of PH on screening tests, presumably due to a peripheral reduction in prostacyclin receptor expression and nitric oxide bioavailability.

Rationale The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. Objectives This post-hoc analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Methods Patients enrolled in INCREASE were analyzed for disease progression events, defined as ≥15% decline in 6-minute walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, ≥10% decline in forced vital capacity, or death during the duration of the 16-week study. Measurements and Main Results 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared to 215 events (109/163 patients, 67%) in the placebo group (p=0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), forced vital capacity decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events) and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared to placebo (35 vs. 58; 22% vs. 36%, p=0.005). Conclusions Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared to placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Idiopathic pulmonary arterial hypertension is associated with high morbidity and mortality. In recent years, the use of targeted therapies has led to an improvement in prognosis. Prostacyclin analogues treprostinil and epoprostenol require continuous subcutaneous or intravenous infusion and are generally administered in a stepwise approach. However, there are no clear recommendations for transition in high-risk patients requiring high doses of prostacyclin analogues. Case summary In this report, we describe the case of a 20-year-old woman under combined treatment with sildenafil, macitentan, and treprostinil who required transition from subcutaneous treprostinil therapy to intravenous epoprostenol due to erratic drug absorption and functional class progression. The transition was performed over 48 h in a stepwise approach reducing treprostinil dose 4 ng/kg/min every 3 h while increasing epoprostenol infusion 2 ng/kg/min until achieving a maintenance dose of 32 ng/kg/min. There were no side effects requiring changes in the infusion rate. Discussion Patients with advanced pulmonary arterial hypertension may necessitate switching from subcutaneous treprostinil to epoprostenol. Although many protocols have been used to date, there are no guidelines to direct this process safely. This 48-h scheme based on the pharmacokinetic properties of each drug was successful and well-tolerated.

Rationale: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin I(2) analogs (beraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of DP1 (D prostanoid receptor subtype 1). Objectives: To study the role of DP1 in the progression of PAH and its underlying mechanism. Methods: DP1 levels were examined in pulmonary arteries of patients and animals with PAH. Multiple genetic and pharmacologic approaches were used to investigate DP1-mediated signaling in PAH. Measurements and Main Results: DP1 expression was downregulated in hypoxia-treated pulmonary artery smooth muscle cells and in pulmonary arteries from rodent PAH models and patients with idiopathic PAH. DP1 deletion exacerbated pulmonary artery remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of the DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted pulmonary artery smooth muscle cell hypertrophy and proliferation in response to hypoxia via induction of mTORC1 (mammalian target of rapamycin complex 1) activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-knockout mice. DP1 activation facilitated raptor dissociation from mTORC1 and suppressed mTORC1 activity through PKA (protein kinase A)-dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting the DP1 receptor. Conclusions: DP1 activation attenuates hypoxia-induced pulmonary artery remodeling and PAH through PKA-mediated dissociation of raptor from mTORC1. These results suggest that the DP1 receptor may serve as a therapeutic target for the management of PAH.

Background Despite advantages in the treatment options of pulmonary arterial hypertension, continuous parenteral prostanoid administration, although often complicated by serious side effects, remains the treatment of choice for patients with advanced disease. The need of transitioning from one parenteral prostanoid agent to the other is often faced in the daily clinical practise. Up to today, there is no established transition protocol from subcutaneous treprostinil to intravenous epoprostenol. Methods A staggered approach to subcutaneous treprostinil down-titration with simultaneous epoprostenol up-titration is described. Subcutaneous treprostinil is down-titrated by 5 ng/kg/min every 5 h while intravenous epoprostenol is up-titrated by 2 ng/kg/min every 2 h. Results The designed protocol was implemented in 4 patients with pulmonary arterial hypertension (3 women, median age 70.5 (range 38–79) years). Median starting subcutaneous treprostinil dose was 44.5 (range 37–100) ng/kg/min and median treprostinil down-titration time was 32.5 (range 25–85) hours. The median maximal epoprostenol dose was 36 (range 28–90) ng/kg/min, achieved in 36 (range 30–90) hours. Only mild prostanoid-related side effects were reported. Conclusions The proposed staggered transition protocol from subcutaneous treprostinil to intravenous epoprostenol was safe in a limited number of patients with pulmonary arterial hypertension.

The intravenous or subcutaneous delivery of prostanoid drugs for moderate to severe pulmonary arterial hypertension has been fraught with complications and patient dissatisfaction. Combination therapy including inhaled treprostinil is an attractive alternative in clinically stable patients. Uncertainties exist about the patient characteristics and the optimal setting (inpatient versus office/home) for transition. Sixteen stable patients with pulmonary arterial hypertension and favorable risk profile were transitioned from parenteral prostanoid to combination therapy including inhaled treprostinil in the home setting. Nine patients were using intravenous treprostinil, two patients were using subcutaneous treprostinil, and five patients were using intravenous epoprostenol at a median dose of 80 (interquartile range, IQR 72–90), 76.5 (68 and 85), and 28 (IQR 26–30) ng/kg/min respectively. Patients were followed up for a median of 732.5 days after transition (IQR 506.5–1294 days). Patients tolerated the transition to inhaled treprostinil well without significant change in functional class (81.25% FC I/II before transition vs. 87.5% after), 6-min walk distance [349 m (IQR 226–461 m) to 364 m (IQR 238–565 m), p = 0.09] or NT-proBNP [149 pg/ml (IQR 71.5–383 pg/ml) to 186.5 pg/ml (IQR 83.5–444 pg/ml), p = 0.38]. Hemodynamic data, where available, showed significant improvements in mean pulmonary artery pressure and pulmonary vascular resistance from 36 mmHg (IQR 27–46.5 mmHg) and 5.2 Wood Units (WU) (IQR 3.1–5.6 WU) to 28.5 mmHg (IQR 22–35.5 mmHg) and 3.2 WU (IQR 2.4–4.2 WU) (p-values 0.022 and 0.003). More patients were on triple therapy after transition, and side effects reported were less severe. For select patients, transition from a parenteral prostanoid-based therapy to a combination regimen including inhaled treprostinil in the home setting appears safe and well tolerated.

Aim: No network meta-analysis has been conducted to study efficacy of drug therapies specific for treatment of pulmonary arterial hypertension in treatment-naive patients only. Methods: Randomized controlled trials on pulmonary arterial hypertension-specific drug therapies were searched and a Bayesian network meta-analysis was performed. The 6-min walking distance (6MWD) and all-cause mortality were efficacy outcomes, whereas discontinuation due to adverse events was a safety-related outcome. Results: Analysis included 3.713 patients from 21 trials. Combination of ambrisentan and tadalafil showed the greatest impact on 6MWD, followed by epoprostenol and intravenous treprostinil (high dose). The latter two demonstrated marked effect size on mortality, although not statistically significant. Conclusion: According to 6MWD, ambrisentan/tadalafil combination was considered as most effective among all comparisons. Prospero ID: CRD42019110832.

Abstract The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. Key messages Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.

Although there is abundant evidence of vascular perturbation from studies of peripheral blood in systemic sclerosis (SSc), there are few data about the ability to use biomarkers of vascular injury and growth factors to predict vascular outcomes and response to therapy. We sought to explore the association between candidate vascular biomarkers and digital ulcerations (DU) in a clinical trial context.We examined 19 circulating vascular, angiogenic, and inflammatory biomarkers in 124 patients with scleroderma and DU who participated in a randomized controlled trial of oral treprostinil diolamine (ClinicalTrials.gov identifier NCT00775463). Correlation, regression, and random forest analyses were conducted to assess biomarker relationships in response to drug treatment.Over the 20-week trial, 82 (66%) patients had their cardinal ulcer completely heal, 54 (44%) developed new ulcers, and 72 (58%) had complete healing of all ulcers; mean change in ulcer burden comparing week 20 with baseline was - 0.36 ± 1.70. Nineteen biomarkers were analyzed for their association and ability to predict clinical DU outcomes. After adjusting for multiple comparisons, no individual biomarker (baseline level, week 20 level, or change over time) was significantly associated with any of the clinical outcomes, suggesting that traditional vascular, angiogenic or inflammatory drivers are not predictive of ulcer fate.The lack of strong response to any of the vascular, angiogenic, or inflammatory markers suggest that these pathways are not primary drivers in the development of DU clinical outcomes in a SSc population with prevalent DU.• Currently we lack robust biomarkers to predict vascular outcomes or response to therapy in scleroderma patients with Raynaud's phenomenon.• Longitudinal assessment of vascular biomarkers in a clinical trial setting provides a unique opportunity to define biomarkers that predict vascular outcomes.• In a randomized controlled trial of oral treprostinil diolamine for treatment of scleroderma-associated digital ulcers, biomarkers involved in several vascular, inflammatory, and angiogenic pathways did not predict short-term clinical response to therapy or digital ulcer outcomes.• Further study of these and other biomarkers should be considered in Raynaud's clinical trials in scleroderma patients without prevalent digital ulcers.

Background: Recently published meta-analyses did not discriminate between drug agents used for initial and sequential combination therapy. Objective: To assess the comparative efficacy of drugs specific for the treatment of pulmonary arterial hypertension (PAH) as add-on therapies based on 6-minute walk distance (6MWD), all-cause mortality, and discontinuation due to adverse events (AEs). Methods: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched until December 9, 2018, for the randomized, placebo-controlled clinical trials (RCTs) conducted on primarily adult patients diagnosed with PAH. Data extracted from applicable RCTs were as follows: for 6MWD mean change from baseline, the total number of patients, and the number of patients with events, per treatment. Network meta-analysis (NMA) was conducted in a Bayesian framework. Results: A total of 16 RCTs were eligible for analysis, with 4112 patients. Add-on therapy with tadalafil or inhaled treprostinil performed better than endothelin receptor antagonists alone [27 m; 95% credible interval (CrI): (11, 43); and 19 m; 95% CrI: (10, 27); respectively]. Add-on therapy with macitentan or bosentan performed better than phosphodiesterase type 5 inhibitors alone [26 m; 95% CrI: (6.4, 45); and 22 m; 95% CrI: (5.1, 38); respectively]. Differences in all-cause mortality and discontinuation due to AEs were nonsignificant. Conclusion and Relevance: Our NMA evaluated efficacy and safety of add-on therapies in patients with PAH. None of the previous meta-analyses evaluated RCTs focusing solely on patients pretreated with another PAH-specific drug therapy. Our results support guideline recommendations on combination therapy in PAH patients and add the quantitative perspective on which sequential therapy demonstrated the greatest effect size.

Background The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period. Methods Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects’ dose). All adverse events and intravascular delivery system complications were evaluated and recorded. Results Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil “leaks” after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery). Conclusion Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk–benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites.

Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease that progresses rapidly and is currently without a cure. Pharmacological treatments aim to slow down disease progression and to reduce symptoms by targeting the prostacyclin, the endothelin or the nitric oxide pathway. Drugs targeting the prostacyclin pathway have been shown to be favourable for PAH patients by causing vasodilatative, anti-proliferative as well as anti-inflammatory effects, but tend to be underused, partially due to adverse effects and difficulties associated with their intravenous administration. Treprostinil, a stable prostacyclin analogue, was FDA-approved in 2002 to improve exercise capacity in PAH patients and is available in intravenous, subcutaneous, inhaled and oral form. The four different possible ways of administration, a long half-life and its stability at room temperature gives treprostinil an advantage over epoprostenol, iloprost and selexipag, the three other FDA-approved drugs targeting the prostacyclin pathway. In clinical trials, treprostinil improved exercise capacity, quality of life (QOL), functional class and clinical status. While the different forms of treprostinil lead to specific complications, its general adverse effects are dizziness, nausea, pain in the jaw and extremities, diarrhoea, flushing and headache. This MiniReview will assess the benefits and drawbacks of treprostinil in the treatment of PAH by examining its specific mechanism of action and pharmacological properties, such as pharmacokinetics, pharmacodynamics, adverse effects and interactions. In addition, we will analyse and discuss results from different clinical trials, comparing treprostinil's four different forms to each other as well as to other drugs targeting the prostacyclin pathway. This article is protected by copyright. All rights reserved.

Over the past 20 years, Pulmonary Arterial Hypertension (PAH) patients and providers have seen an increase in options to treat PAH. Currently, there are choices for the delivery of medications approved to treat patients with PAH where at one point the only option was intravenous (IV) therapy. This case study details the transition from IV Epoprostenol to oral Treprostinil for the treatment of a 53 year old female diagnosed with severe Pulmonary Arterial Hypertension whose quality of life became unbearable by the IV medication delivery route. This patient was a synchronized swimmer in her youth and her passion for water activities continued throughout her short life. After her diagnosis of severe PAH, her life abruptly changed as she was placed on triple therapy, which consisted of an endothelin receptor antagonist (ERA), a phosphodiesterase-5 inhibitor (pde-5), and the IV epoprostenol. The patient experienced severe side effects that negatively impacted her ability to resume her activities of daily life and swimming. Although she remained hemodynamically stable on IV therapy, her poor quality of life and severe depression convinced her cardiologist that transitioning to an oral treprostinil would be the only option for her survival. At the time, there was a lack of clinical trials or guidelines to support the transition from IV to oral prostacyclins to follow, so an interdisciplinary team approach needed to be taken to ensure that the safety and efficacy of the transition would be maintained.

Pulmonary arterial hypertension is a progressive, incurable disease that occurs in adults and children alike. Therapeutic options for children are limited and infrequently described, including newer agents such as treprostinil, an oral prostanoid. Herein, we describe the pooled pediatric experience in 28 patients from four pediatric pulmonary hypertension programs over two years. This descriptive, observational study describes the various methods of initiation of oral treprostinil in both prostanoid-naïve patients and those transitioning from parenteral or inhaled prostanoids. The youngest patient was four years old and the smallest weighed 16 kg. We describe adverse reactions and their management. Most patients in this study (27/28) were able to successfully initiate therapy. However, gastrointestinal adverse reactions were common; half of the patients started on this therapy had discontinued it within the two-year study period.

Purpose of review Pulmonary vascular disease resulting in pulmonary hypertension in the context of interstitial lung disease (PH-ILD) is a common complication that presents many challenges in clinical practice. Despite recent advances, the pathogenetic interplay between parenchymal and vascular disease in ILD is not fully understood. This review provides an overview of the current knowledge and recent advances in the field. Recent findings Clinical trials employing the phosphodiesterase-5-inhibitor sildenafil delivered negative results whereas riociguat showed harmful effects in the PH-ILD population. More recently, inhaled treprostinil showed positive effects on the primary endpoint (six-min walk-distance) in the largest prospective randomized placebo-controlled trial to date in this patient population. Additionally, a pilot trial of ambulatory inhaled nitric oxide suggests beneficial effects based on the novel endpoint of actigraphy. Summary In view of these novel developments this review provides an overview of the status quo of screening, diagnosis and management of pulmonary vascular disease and PH in patients with ILD.

Purpose Epoprostenol and treprostinil are prostacyclins indicated for the treatment of pulmonary arterial hypertension (PAH). Although there is literature describing the conversion of intravenous (IV) epoprostenol to IV treprostinil or IV treprostinil to oral treprostinil, there is little data on the direct conversion of IV epoprostenol to oral treprostinil. In this case, we describe the direct conversion of IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. Summary A 39 year-old female with PAH was admitted for altered mental status and self-removal of her peripherally inserted central catheter (PICC) used for IV epoprostenol. Given the unplanned hospitalization, absence of a dedicated central line for IV prostacyclin therapy, and concern the patient may remove a future subcutaneous line, the patient was transitioned to oral treprostinil. Of note, despite triple PAH therapy, the patient was unable to reach a low risk group based on her prognostic risk assessment. A right heart catheterization four months prior found severe PAH with a pulmonary arterial pressure of 79/32 mmHg (mean, 49 mmHg) and pulmonary vascular resistance of 10.6 Wood units. To expedite the transition, the patient was directly converted from IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. A target oral treprostinil dose of 5 mg TID was calculated based on 110% of the IV epoprostenol dose (19 ng/kg/min) utilizing the conversion recommended by the medication manufacturer. Every 8 hours, IV epoprostenol was decreased by 2 ng/kg/min and oral treprostinil was increased by 0.5 mg. The target oral treprostinil dose of 5 mg TID was reached 72 hours after conversion initiation. Three hours after the final titration, the patient was discharged home on room air. Conclusion In this case, rapid transition from IV epoprostenol to oral treprostinil was achieved in 72 hours without reported adverse effects.

BACKGROUND: Application of Treprostinil (TRE) in the patients with single ventricle (SV) physiology is very limited, and the optimal dose for children has not been determined. In this study, we aimed to analyze plasma samples to assess the attainment of clinically therapeutic concentrations of TRE and its efficacy and safety in the treatment of pediatric functional SV pulmonary arterial hypertension (FSV-PAH).. METHODS: Pediatric patients with FSV-PAH were recruited in this study. IV TRE at an initial rate of 5 ng/kg/min was administered through the femoral vein with an increase in rate to 10 ng/kg/min every 30 minuntil the aiming dose of 80 ng/kg/min had been reached. The drug was gradually discontinued after 12 h of treatment at a stable dose. The mean postoperative pulmonary artery pressure (mPAP), pulmonary-to-systemic arterial pressure ratio (Pp/Ps), and the ratio between arterial oxygen partial pressure and inhaled oxygen concentration (PaO(2)/FiO(2)) were used to evaluate the efficacy of TRE treatment. A multiple linear regression model was used to explore the relevant factors associated with TRE blood concentration. RESULTS: A total of eight patients were enrolled in the investigation, with an age range of 2.5–9.9 years. The median stable dose of TRE was 70 ng/kg/min with a range of 55–75 ng/kg/min. The median subliminal dose was 55 ng/kg/min with a range of 25–75 ng/kg/min. A linear relationship was established between the TRE dose and the plasma concentration. TRE blood concentrations were associated with dose and patient height. After TRE treatment, mPAP, Pp/Ps, and PaO(2)/FiO(2) were significantly improved (P