Effect of epoprostenol-induced thrombocytopaenia on lung transplantation for pulmonary arterial hypertension.

OBJECTIVES: Preoperative intravenous epoprostenol therapy can cause thrombocytopaenia, which may increase the risk of perioperative bleeding during lung transplantation. This study aimed to determine whether lung transplantation can be safely performed in patients with epoprostenol-induced thrombocytopaenia. METHODS: From June 2008 to July 2022, we performed 37 lung transplants in patients with pulmonary arterial hypertension (PAH), including idiopathic PAH (n = 26), congenital heart disease-associated PAH (n = 7), pulmonary veno-occlusive disease (n = 3) and peripheral pulmonary artery stenosis (n = 1) at our institution. Of these, 26 patients received intravenous epoprostenol therapy (EPO group), whereas 11 patients were treated with no epoprostenol (no-EPO group). We retrospectively analysed the preoperative and postoperative platelet counts and post-transplant outcomes in each group. RESULTS: Preoperative platelet counts were relatively lower in the EPO group than in the no-EPO group (median EPO: 127 000 vs no-EPO: 176 000/µl). However, blood loss during surgery was similar between the 2 groups (EPO: 2473 ml vs no-EPO: 2615 ml). The platelet counts significantly increased over 1 month after surgery, and both groups showed similar platelet counts (EPO: 298 000 vs no-EPO: 284 000/µl). In-hospital mortality (EPO: 3.9% vs no-EPO: 18.2%) and the 3-year survival rate (EPO: 91.4% vs no-EPO: 80.8%) were similar between the 2 groups. CONCLUSIONS: Patients with PAH treated with intravenous epoprostenol showed relatively lower platelet counts, which improved after lung transplantation with good post-transplant outcomes.

Epoprostenol (Prostacyclin Analog) as a Sole Anticoagulant in Continuous Renal Replacement Therapy for Critically Ill Children With Liver Disease: Single-Center Retrospective Study, 2010-2019.

OBJECTIVES: Despite deranged coagulation, children with liver disease undergoing continuous renal replacement therapy (CRRT) are prone to circuit clotting. Commonly used anticoagulants (i.e., heparin and citrate) can have side effects. The aim of this study was to describe our experience of using epoprostenol (a synthetic prostacyclin analog) as a sole anticoagulant during CRRT in children with liver disease. DESIGN: Single-center, retrospective study, 2010-2019. SETTING: Sixteen-bedded PICU within a United Kingdom supra-regional center for pediatric hepatology. PATIENTS: Children with liver disease admitted to PICU who underwent CRRT anticoagulation with epoprostenol. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Regarding CRRT, we assessed filter life duration, effective 60-hour filter survival, and effective solute clearance. We also assessed the frequency of major or minor bleeding episodes per 1,000 hours of CRRT, the use of platelet and RBC transfusions, and the frequency of hypotensive episodes per 1,000 hours of CRRT. In the 10 years 2010-2019, we used epoprostenol anticoagulation during 353 filter episodes of CRRT, lasting 18,508 hours, in 96 patients (over 108 admissions). Median (interquartile range [IQR]) filter life was 48 (IQR 32-72) hours, and 22.9% of filters clotted. Effective 60-hour filter survival was 60.5%.We identified that 5.9% of filters were complicated by major bleeding (1.13 episodes per 1,000 hr of CRRT), 5.1% (0.97 per 1,000 hr) by minor bleeding, and 11.6% (2.22 per 1,000 hr) by hypotension. There were no differences in filter life or clotting between patients with acute liver failure and other liver diseases; there were no differences in rates of bleeding, hypotension, or transfusion when comparing patients with initial platelets of ≤ 50 × 109 per liter to those with a higher initial count. CONCLUSIONS: Epoprostenol, or prostacyclin, as the sole anticoagulant for children with liver disease receiving CRRT in PICU, results in a good circuit life, and complications such as bleeding and hypotension are similar to reports using other anticoagulants, despite concerns about coagulopathy in this cohort.

Treprostinil Effectiveness in Higher-Risk Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension.

BACKGROUND: Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy. METHODS: Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy. RESULTS: Forty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes. CONCLUSIONS: Treprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds.

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. METHODS: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. RESULTS: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV. CONCLUSION: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01560637.

Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality.

OBJECTIVE: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). METHODS: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs. RESULTS: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively. CONCLUSION: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD.

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. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry treprostinil into the airways, with a high fraction of the particles in the respirable range. In a clinical study in patients with pulmonary arterial hypertension, Tyvaso DPI had similar exposure and pharmacokinetics, low incidence of adverse events, and high patient satisfaction compared with nebulized treprostinil solution. Tyvaso DPI may be considered as a first prostacyclin agent or for those that do not tolerate other prostacyclin formulations, patients with pulmonary comorbidities, patients with mixed Group 1 and Group 3 pulmonary hypertension, or those that prefer an active lifestyle and need a portable, non-invasive treatment. Tyvaso DPI is a patient-preferred, maintenance-free, safe delivery option that may improve patient compliance and adherence.

Transition from Intravenous Epoprostenol to Treprostinil Due to Intolerable Side Effects in Patients With Pulmonary Arterial Hypertension.

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, it has side effects. Reviewing the side effects associated with epoprostenol and treprostinil is essential for improving the long-term treatment strategies for PAH. This retrospective review included patients with PAH who transitioned from intravenous epoprostenol to intravenous treprostinil owing to intolerable side effects, including high cardiac output symptoms, ascites, and thrombocytopenia. Of the 85 patients who received epoprostenol at our hospital between 2013 and 2021, 16 (11 women), with a median age of 33 (range 26 to 40) years (including 12 with idiopathic PAH, 3 with hereditary PAH, and 1 with connective tissue disease pulmonary hypertension), had to switch from intravenous epoprostenol to treprostinil owing to the side effects. After transitioning, epoprostenol-associated intolerable side effects, such as high cardiac output symptoms, ascites, and thrombocytopenia, were ameliorated. In conclusion, for patients with PAH who have intolerable side effects from epoprostenol and have difficulty in continuing treatment, switching from epoprostenol to treprostinil may be an option. Switching treatment leads to better adherence and improved long-term prostacyclin therapy.

Safety and efficacy of transitioning from selexipag to oral treprostinil in pulmonary arterial hypertension: Findings from the ADAPT registry.

PURPOSE: Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil. METHODS: ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions. RESULTS: Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging. CONCLUSION: Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Incidence of Bloodstream Infection in Patients with Pulmonary Hypertension under Intravenous Epoprostenol or Iloprost-A Multicentre, Retrospective Study.

Intravenous synthetic prostacyclin analogs (iPCAs), such as epoprostenol, treprostinil and iloprost have been widely used for the treatment of pulmonary arterial hypertension (PAH). Despite having good outcomes, continuous infusion of iPCAs has been associated with some adverse effects. Bloodstream infection (BSI) is one of the most severe complications, although poorly recognized, especially under iloprost administration, which few studies have addressed. This study aimed to compare the BSI incidence rates between intravenous iloprost and epoprostenol administration. Patients with pulmonary hypertension (PH) functional class III or IV receiving intravenous iloprost or epoprostenol through Hickman catheter, between 2004 and 2019, were retrospectively selected from two PH treatment centers. From a total of 36 patients (13 for iloprost and 23 for epoprostenol), 75% (n = 27) fulfilled the PAH criteria, mainly belonging to the idiopathic group. Overall BSI rate was 1.5/1000 days of treatment (3.38 and 0.09/1000 days for iloprost and epoprostenol, respectively). Patients receiving iloprost were at a higher risk of developing BSI than those receiving epoprostenol (HR: 12.5; 95% CI: 1.569-99.092). A higher mortality rate from BSI was also identified in the iloprost group (p = 0.04). Twenty-seven patients developed BSI, with 92% of them requiring hospitalization. A total of 29 agents were found, 10 Gram-positive (mainly Staphylococcus aureus; n = 5) and 19 Gram-negative (mainly Pseudomonas aeruginosa; n = 6) bacteria. Iloprost administration was linked to a significantly higher incidence of BSI, worse prognosis, and more BSI-related deaths than epoprostenol. BSI due to Gram-negative, commensal, low-virulence bacteria was also higher in the iloprost group. In short, physicians should be aware when prescribing iPCA to guarantee their patients' safety and best medical care.

Pulmonary hypertension inhaled therapies: An updated review.

Treatments of pulmonary hypertension (PH) continue to evolve with approval of new therapies. The currently FDA approved inhaled PH therapies include inhaled iloprost for group 1 pulmonary arterial hypertension (PAH), inhaled treprostinil solution and treprostinil dry powder inhaler for both group 1 PAH and group 3 PH associated with interstitial lung disease (PH-ILD). Inhaled treprostinil was recently approved for group 3 PH-ILD based on the results of INCREASE trial and the newer formulation of treprostinil dry powder that comes with a new inhaler was recently approved for both group 1 PAH and group 3 PH-ILD based on BREEZE study. The pipeline for inhaled PH therapies includes several promising molecules that can enrich the current PH therapeutic era and mitigate several systemic side effects by directly delivering the drug to the target organ. In this review article we summarize the evidence for the currently approved inhaled PAH/PH therapies, discuss the available inhalation devices, present a roadmap for successful treatment strategy, and present several inhaled PAH/PH therapies in the pipeline.

Inhaled prostacyclin therapy in the acute respiratory distress syndrome: a randomized controlled multicenter trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. METHODS: We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. RESULTS: Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. CONCLUSIONS: The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. TRIAL REGISTRATION: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Tolerability, safety and survival in patients with severe pulmonary arterial hypertension treated with intravenous epoprostenol (Veletri®): a prospective, 6-months, open label, observational, non-interventional study.

BACKGROUND: Epoprostenol AS (Veletri®), a thermostable epoprostenol formulation, provides better drug stability and improved clinical use compared to previous epoprostenol formulations. This study aims to expand clinical experience in the use of Veletri®, especially regarding tolerability, safety and survival. METHODS: Pulmonary arterial hypertension (PAH) patients at high risk despite pretreatment with at least double oral combination therapy and with clinical indication for epoprostenol (Veletri®) treatment were consecutively included in this prospective, open label, observational, non-interventional study. Clinical data were assessed at baseline, after 3 and 6 months. Adverse events (AEs) and serious adverse events (SAEs) were documented. Survival from initiation of Veletri® was assessed at last patient out. RESULTS: Fifteen patients (60 ± 13.7 years, WHO functional class III (n = 10) or IV (n = 5), severely impaired right ventricular function, mean pulmonary arterial pressure 54.8 ± 8.9 mmHg, mean pulmonary vascular resistance 4.4 ± 0.7 (median 3.8) Wood Units) were enrolled and treated with a mean dosage of 7.9 ± 3.9 (median 7.5) ng/kg/min. Eleven patients completed the study (treatment withdrawal n = 1, death n = 3). After a mean follow-up of 19.1 ± 13.5 (median 18.0) months, seven patients died and three were listed for lung transplantation. Seven AEs (nausea n = 3, diarrhea n = 1, flushing n = 2, headaches n = 1) and three SAEs (catheter infection n = 2, catheter occlusion n = 1) were related to Veletri®. The 1- and 2-year survival rates were 73.3% and 52.4%, respectively. CONCLUSIONS: The study showed that safety and tolerability of epoprostenol AS (Veletri®) was comparable to previous prostacyclin formulations and was feasible for most patients. The maximum tolerable dosage was lower than dosages reported in the literature. In future applications/trials the up-titration process should be pushing for higher dosages of epoprostenol in the occurrence of side effects, as the achievement of a high and effective dosage is crucial for the clinical benefit of the patients. Survival was as expected in these prevalent severely impaired patients. Trial registration The study was registered in the EUPAS registry (EUPAS32492).

Efficacy and safety of non-prostanoid prostacyclin receptor agonist for pulmonary hypertension: A meta-analysis.

BACKGROUND: Oral non-prostanoid prostacyclin receptor agonists therapies have been recommended for pulmonary arterial hypertension in many countries. OBJECTIVE: We aimed to evaluate the specific impact of non-prostanoid prostacyclin receptor agonists on pulmonary hypertension and to explore the influence of study characteristics on results. METHODS: PubMed, Embase, and ClinicalTrials.gov were systematically searched from inception to July 12, 2022. Randomized controlled trials comparing non-prostanoid prostacyclin receptor agonists administration with placebo for treating pulmonary hypertension were included. Two researchers independently selected eligible studies, assessed the bias risk and extracted related data. RevMan5.1 was used for performing the statistical analysis and the assessment of bias risk of the enrolled studies. PROSPERO registered number CRD42022304172. RESULTS: Seven trials involving 1727 patients were included. Pooled analyses indicated non-prostanoid prostacyclin receptor agonists significantly reduced clinical worsening events (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.54 to 0.74), increased 6-min walk distance (mean difference [MD], 10 m; 95% CI, 3-17 m), decreased pulmonary vascular resistance (MD, -121 dyn s/cm5; 95% CI, -172 to -69 dyn s/cm5) and increased cardiac index (MD, 0.38 L/min/m2; 95% CI, 0.26-0.50 L/min/m2) compared with the control. No significant differences in all-cause mortality (RR, 0.86; 95% CI, 0.26 to 2.78), NYHA/WHO functional class (RR, 1.16; 95% CI, 0.61 to 2.18), mean pulmonary artery pressure (MD, -0.88 mmHg; 95% CI, -2.20 to 0.44 mmHg), right atrial pressure (MD, 0.66 mmHg; 95% CI, -0.59 to 1.90 mmHg) and total adverse events (RR, 1.05; 95% CI, 0.99 to 1.10) were found between non-prostanoid prostacyclin receptor agonists group and control group. CONCLUSION: Non-prostanoid prostacyclin receptor agonists treatment exerted benefits on clinical worsening, pulmonary vascular resistance, and cardiac index in pulmonary hypertension patients, without increasing the incidence of total adverse events.

The "Flolan Rash": An Impressively Asymptomatic and Non-Inflammatory Eruption Following Long-Term Epoprostenol Therapy.

Epoprostenol (Flolan) is a last-resort intravenous medication for the treatment of severe pulmonary arterial hypertension (PAH). Cutaneous adverse events of Flolan are well-known by pulmonologists, though lacking in dermatologic literature. We report a near erythrodermic appearing, yet asymptomatic eruption lasting 10 years in a woman with end-stage PAH treated with long-term intravenous epoprostenol. Non-pruritic, blanching, erythematous papules coalescing to plaques surrounded by a hypopigmented halo encompassed her entire torso, as well as bilateral upper and lower extremities. Additional findings included bright red palms and soles associated with pain and tingling while walking. Laboratory workup revealed thrombocytopenia and a slightly elevated erythrocyte sedimentation rate (ESR); connective tissue disease markers were negative. Skin biopsies were, surprisingly, largely unremarkable without an inflammatory infiltrate. The patient was trialed on topical clobetasol ointment without effect. Her striking, yet asymptomatic and non-inflammatory eruption was thought due to long-term use of epoprostenol, a last-resort synthetic prostacyclin used to treat severe PAH. As her cutaneous findings were not bothersome, her dose of Flolan was not lowered and her lower extremity pain was treated with gabapentin. With this case, we aim to increase awareness of the impressive “Flolan rash”, a persistent erythematous eruption well-known by pulmonologists, yet scarcely described in dermatologic literature. Significant Finding: We report a striking, yet asymptomatic and non-inflammatory skin eruption lasting 10 years presumed due to long-term use of epoprostenol for end-stage pulmonary arterial hypertension. Meaning: Cutaneous adverse events of intravenous epoprostenol are well-known by pulmonologists, though lacking in dermatologic or primary care literature. The extensive body surface involvement, and near erythroderma, associated with Flolan necessitates awareness by patients, dermatologists, and other healthcare providers outside of the field of pulmonology. J Drugs Dermatol. 2022;21(11):1249-1251. doi:10.36849/JDD.6821.

Safety, Tolerability, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder for Pulmonary Hypertension: A Phase 1, Randomized, Double-Blind, Single- and Multiple-Dose Study.

INTRODUCTION: Treprostinil is a prostacyclin vasodilator widely used for the treatment of pulmonary arterial hypertension (PAH) and, in its inhaled form, for pulmonary hypertension associated with interstitial lung disease (PH-ILD). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil (TP), an ester prodrug of treprostinil. TPIP is designed to provide sustained release of treprostinil in the lung over a prolonged period, potentially enabling a once-daily (QD) dosing regimen and significantly higher tolerated doses compared with currently available treprostinil formulations. This phase 1 study assessed the safety, tolerability, and pharmacokinetics of TP and treprostinil following single and multiple QD administrations of TPIP in healthy volunteers. METHODS: Healthy adults (aged 18-45 years) were randomized to receive single or multiple QD inhalation doses of TPIP. Participants in the single-dose phase received TPIP 112.5, 225, 450, or 675 µg (n = 6/dose) or placebo (n = 2). Participants in the multiple-dose phase received TPIP 225 µg QD for 7 days (n = 6), 112.5 µg QD for 4 days followed by 225 µg QD for 3 days (n = 6), or placebo for 7 days (n = 4). RESULTS: Overall, 41 of 42 participants (97.6%) completed the study. In the single-dose phase, 70.8% (n = 17/24) of TPIP-treated participants experienced a treatment-emergent adverse event (TEAE) vs 0% (n = 0/2) of placebo-treated participants; the most common TEAEs (≥ 20%) were cough (45.8%), dizziness (29.2%), and throat irritation (20.8%). In the multiple-dose phase, 83.3% (n = 10/12) of TPIP-treated participants experienced a TEAE vs 50.0% of placebo-treated participants (n = 2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), chest discomfort (33.3% vs 0%), and dizziness (25.0% vs 0%). Most TEAEs were mild; only seven patients experienced a moderate TEAE, and no severe or serious TEAEs occurred. In the multiple-dose phase, participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 225 µg QD at treatment initiation (66.7% vs 100.0%), and all TEAEs with dose titration were mild. After a single dose of TPIP, treprostinil elimination t1/2 was 8.67-11.6 h and exposure was dose proportional, with mean (CV%) Cmax 78.4-717 pg/mL (38.6-72.9%) and AUC0-∞ 1090-5480 pg·h/mL (11.5-30.0%). At steady state (TPIP 225 µg), the mean (CV%) of Cmax, Cmin, and AUCτ were 193-228 pg/mL (32.9-46.4%), 17.6-22.8 ng/mL (43.7-64.4%), and 1680-1820 pg·h/mL (28.7-36.6%), respectively. The elimination t1/2 was 6.84-8.82 h after repeat dosing. No steady-state accumulation was observed. Plasma concentrations of TP were below the limit of quantification (100 pg/mL) at all time points measured. CONCLUSION: TPIP was well tolerated at the doses tested, and dose titration improved tolerability. Treprostinil pharmacokinetics were linear and supportive of a QD treatment regimen. These results support further development of TPIP in patients with PAH and PH-ILD.

A retrospective review of implementation of an inhaled epoprostenol protocol in the emergency department.

INTRODUCTION: Inhaled epoprostenol is a selective pulmonary vasodilator that has shown a potentially broad number of applications in the management of critically ill patients. To date, the vast majority of the literature with regard to efficacy, indications for use, and adverse effects of inhaled epoprostenol is focused on use of this agent in critical care settings, with relatively little literature describing use of inhaled epoprostenol in the Emergency Department. This retrospective review sought to examine instances in which inhaled epoprostenol was administered in the Emergency Department of a tertiary-care, Level I trauma center following implementation of a clinical pathway for administration of this medication for cases of refractory hypoxemia, RV dysfunction, and refractory hypoxemia. Primary outcomes were monitoring for adverse effects (i.e. hypotension), trend in FiO2 requirement over time, and clinical indication for initiation of inhaled epoprostenol. METHODS: An automated review was performed to query cases in which inhaled epoprostenol had been initiated in the Emergency Department following adoption of the inhaled epoprostenol clinical pathway. Cases were excluded if the medication was initiated in the prehospital setting, ordered but not administered, or administered for a period of <1 h. Vital signs and co-administration of vasopressors were followed before and following epoprostenol administration to assess for change over time. Clinical indication of epoprostenol administration was assessed via manual chart review. RESULTS: Inhaled epoprostenol was administered in 20 instances, with 15 cases ultimately meeting inclusion criteria. There were no cases of clinically significant hypotension (MAP <65) in any of the cases in which inhaled epoprostenol was administered in the Emergency Department, and mean vasopressor requirement did not increase over time. A majority of patients saw a reduction in FiO2 requirement following administration of inhaled epoprostenol. The most common indication for initiation of inhaled epoprostenol based on manual chart review was pulmonary embolism. DISCUSSION: In this review of cases in which inhaled epoprostenol was administered following adoption of a clinical pathway for medication administration, there were no cases of hypotension or other adverse effects that appear to be attributable to medication administration. Pulmonary embolism and refractory hypoxemia were the most common noted indications for administration of inhaled epoprostenol. Further research is warranted regarding development of clinical protocols for administration of inhaled pulmonary vasodilators in the Emergency Department setting.

Pancreatic enlargement in a patient receiving therapy with vasodilators for pulmonary arterial hypertension: a case report.

Epoprostenol is a prostacyclin (prostaglandin I2) analog that causes vasodilation and inhibits platelet aggregation and is used in the management of severe pulmonary arterial hypertension (PAH). We herein report a patient with PAH who developed pancreatic enlargement after the initiation of therapy including epoprostenol. Although it is well known that thyroid enlargement occurs in patients with PAH receiving epoprostenol therapy, the pancreatic findings associated with epoprostenol therapy have not been well described. Although the size of the pancreas was clearly increased, there was no blood data or symptoms suggestive of abnormal pancreatic function and pancreatitis, and the patient's abdominal complaints improved quickly, despite the continuation of epoprostenol therapy. Eleven months after the start of continuous intravenous epoprostenol infusion therapy, the pancreatic enlargement was still evident on imaging, but there were no abdominal symptoms or elevated pancreatic enzymes. This case highlights the fact that epoprostenol therapy may cause pancreatic changes that mimic acute or autoimmune pancreatitis.

A pilot study to evaluate the safety and efficacy of treprostinil in the treatment of calcinosis in systemic sclerosis.

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 (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score and patient/physician assessment of calcinosis severity. 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.

Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.

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.

Epoprostenol for the treatment of pulmonary arterial hypertension.

Introduction: Pulmonary arterial hypertension (PAH) is a rare, progressive, and severe disease. Since the first demonstration of survival benefit of intravenous epoprostenol in monotherapy in 1996, prostanoids remain the cornerstone for PAH patients at high risk. This review is essential to understand the current situation of this drug among all the therapeutic possibilities concerning this entity.Areas covered: The aim of this article is to review the pharmacological properties of epoprostenol and to update its clinical evidence in different specific clinical scenarios. A deep literature search was carried out on the MEDLINE database for published literature before March 2021.Expert opinion: Epoprostenol is still the best treatment option for high-risk PAH patients. Nevertheless, there are many unsolved questions: drug dosing, its use in combination therapy with other pulmonary vasodilators, and the utility in PAH associated with connective tissue disease, congenital heart disease, or pulmonary veno-occlusive disease are only a few examples. Its safety and efficacy are supported by clinical trials, observational work, and experience, both as monotherapy and in combination therapy. Epoprostenol should be considered a destination treatment in high-risk patients and not only as a bridge to pulmonary transplantation. However, it remains underused in clinical practice.