Prostacyclin Therapy Research Articles

A network meta-analysis on the vasomodulators for portopulmonary hypertension

Abstract Background In patients with portopulmonary hypertension (PoPH) who are eligible and awaiting liver transplant, guidelines recommend lowering pulmonary pressures with vasomodulators as a bridge to transplant. However, efficacy of each vasomodulator class as a bridge to transplant remains unknown. Purpose This review compares the use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 inhibitors (PDE5-I), prostacyclin (PC) and combination therapy in its pulmonary pressure-lowering effects and pre-transplant mortality in this strictly selected subset of patients. Methods A search conducted on Medline and Embase on articles relating to vasomodulator use in PoPH for pulmonary pressure-lowering effects and mortality. Network analysis was conducted to summarize the evidence. Surface under the cumulative ranking curve (SUCRA) was used to rank treatments. Results Ten studies with 180 patients were included. SUCRA analysis demonstrated largest mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) lowering effects in ERA and combination therapy, followed by PDE5-I and PC. mPAP-lowering effects were largest in ERA (MD −19.440, CI: −62.280 to 23.400) and combination therapy (MD −18.223, CI: −29.677 to −6.770) when compared to PDE5-I (table 1). Pre-transplant mortality were comparable between ERA, PDE5-I and combination therapy. Both ERA (RR:0.349. CI: 0.137–0.891) and PDE5-I (RR: 0.279, CI: 0.091–0.854) had significantly lower mortality than PC (table 2). Conclusion This meta-analysis provides preliminary evidence that ERA have shown larger pulmonary pressure-lowering effects than PDE5-I in PoPH patients who were eligible for LT. Both ERA and PDE5-I have comparable mortality outcomes, with unfavorable outcomes in PC users. Funding Acknowledgement Type of funding sources: None.

HEALTH OUTCOMES AND COSTS ASSOCIATED WITH ORAL TREPROSTINIL AND SELEXIPAG ONE YEAR INTO TREATMENT: A UNITED STATES CLAIMS DATABASE ANALYSIS IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: Previous comparisons of oral treprostinil (TRE) and selexipag (SLX) using real-world data have been limited to short duration follow-up periods or have used models to estimate healthcare costs. This analysis aims to characterize various outcomes and direct healthcare costs for pulmonary arterial hypertension (PAH) patients being treated with TRE or SLX 1-year into treatment. METHODS: A retrospective analysis was completed using the IBM® MarketScan® Research Databases from January 2014 to June 2019. Patients were required to have a pulmonary hypertension inpatient or outpatient medical claim identified by International Classification of Disease Codes (ICD-9-CM: 416.0, 416.8, 416.9; ICD-10-CM: I27.0, I27.20, I27.21, I27.29, I27.81, I27.83, I27.89, I27.9) plus a prescription claim for TRE or SLX. The index date was defined as the day of the first claim for TRE or SLX. Patients were ≥18 years old and required to have a PH medical claim in the 6-month pre-index, continuous health insurance enrollment 6 months pre-index and 12 months post-index. Adherence was defined as having a medication possession ratio (MPR) ≥80% and persistence was defined by continuous therapy in the 1-year follow-up period without a medication gap of ≥60 days. RESULTS: 120 patients in the TRE cohort and 155 patients in the SLX cohort met inclusion criteria. Patients were of similar age (TRE: mean [SD] = 57.0 [16.1] vs. SLX: 57.2 [13.5]), similar sex (TRE: 70% female vs. SLX: 77.4%) and had a similar Charlson Comorbidity Index (CCI) score (TRE: mean [SD] 3.5 [2.6] vs. SLX: 3.1 [2.0]). Concomitant PAH therapies received during the pre-index period were generally similar between cohorts, however, more patients on TRE compared to SLX (11.7% vs. 2.6%, p=0.003) transitioned from parenteral PAH treatment. In the 1-year following treatment, adherence and persistence were comparable: adherence was 83% for TRE and 81% for SLX (p=0.567) and persistence was 53% for TRE and 59% for SLX (p=0.373). Among the patients persistent on therapy at 1-year, median (IQR) annual pharmacy costs were $232,071 ($211,039-$256,402) for SLX compared with $107,511 ($45,647-$186,622) for TRE (p<0.01) representing 116% higher median annual pharmacy costs for SLX. A similar proportion within each group switched to parenteral prostacyclin therapy (TRE: 6.7% vs SLX: 5.2%, p=0.794) or inhaled prostacyclin therapy (TRE: 3.3% vs SLX: 3.2%, p=1.0) in the 1-year follow-up period. After adjusting for baseline differences between cohorts, total mean PAH-related healthcare costs (pharmacy + medical) in the 1-year follow-up period were $350,782 ($307,873-$394,849) for SLX compared to $229,564 ($198,791-$264,944) for TRE (p<0.05). CONCLUSIONS: Real-world claims data show similar utilization and outcomes for TRE and SLX in patients with PAH with notable differences in costs in the 1-year following treatment initiation. CLINICAL IMPLICATIONS: Cost differences between TRE and SLX should be considered when selecting oral prostacyclin therapies given the broader economic impact on the U.S. healthcare system as well as potential costs specific to health insurers, pharmacy-benefit managers, employers, and patients. DISCLOSURES: Employee relationship with United Therapeutics Please note: >$100000 by Peter Classi, source=Web Response, value=Salary Consultant relationship with United Therapeutics Please note: 2020-current Added 04/27/2021 by Bonnie Dean, source=Web Response, value=Grant/Research Support Employee relationship with United Therapeutics Please note: 2017 to Present Added 04/27/2021 by Alex DeRuiter, source=Web Response, value=Salary Employee relationship with Xcenda, LLC Please note: 01/04/2020 Added 04/30/2021 by Henry Lee, source=Web Response, value=Salary Employee relationship with United Therapeutics Corporation Please note: >$100000 by Kellie Morland, source=Web Response, value=Salary Employee relationship with Xcenda LLC Please note: Jan 1, 2020 Added 04/27/2021 by Dana Stafkey-Mailey, source=Web Response, value=UT provided Xcenda Fin Support Employee relationship with United Therapeutics Corporation Please note: 11 Months Added 04/27/2021 by Benjamin Wu, source=Web Response, value=Salary

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

TRANSITIONING FROM PARENTERAL PROSTACYCLIN THERAPY TO ORAL SELEXIPAG IN PULMONARY ARTERIAL HYPERTENSION

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious condition that confers a poor prognosis if not promptly diagnosed and treated. Although parenteral medications targeting the prostacyclin pathway are often prescribed for high-risk patients, the transition to a more convenient and tolerable medication acting on the same pathophysiologic pathway may provide significant benefit in patients with stable disease who are burdened by the multiple complications inherent to parenteral therapy. CASE PRESENTATION: Three patients were successfully transitioned from parenteral prostacyclin therapy to selexipag at a single tertiary-care, expert pulmonary hypertension centre. Prior to transition, two patients were prescribed subcutaneous treprostinil and one intravenous epoprostenol. Reasons for transition included severe site pain with subcutaneous therapy, recurrent line infections, and patient preference. All patients were functional class II at time of transition. Right heart catheterization pre-transition demonstrated pre-capillary pulmonary hypertension in two patients (mPAP of 33mmHg with PVR of 5.2WU in the first, and mPAP of 32mmHg with PVR of 6.3WU in the second), with normal hemodynamics in the third. Transitions were performed in the outpatient setting over the course of 4-8 weeks. All patients achieved maximum daily dosing of selexipag (3200mcg) at the end of transition, with each patient experiencing temporary side effects during transition, e.g. headache, jaw pain, diarrhea, nausea, myalgias, limb pain, and peri-orbital edema. Following transition, there was no incidence of mortality (PAH or otherwise), PAH-related hospitalizations, re-initiation of parenteral therapy, or worsening of functional class or 6-minute walk distance in any of the three patients within 36 months of follow-up (in 6-, 12-, 24-, and 36- months intervals). Echocardiographic and right heart catheterization parameters were stable post-transition. DISCUSSION: All three patients were successfully transitioned from parenteral prostacyclin therapies to selexipag as evidenced by a lack of death, hospitalizations, and/or failure of oral therapy, as well as stability in various functional, echocardiographic, and hemodynamic outcomes with up to 36-months of follow-up. While parental prostacyclin analogues are still required for patients with high-risk or refractory disease, the patients in this study were those who were clinically and hemodynamically stable pre-transition with infusion-related morbidity. This may reflect the phenotype of patient where transition could be considered. CONCLUSIONS: In a carefully selected patient population with PAH on parenteral prostacyclin therapy, transition to selexipag may be a safe and viable option. Further studies are required to better delineate baseline predictors of long-term therapeutic efficacy and safety in a real-world PAH population. REFERENCE #1: Chin KM, McLaughlin V, Kim NH, et al. Clinical Course of Patients Transitioned from Another Prostacyclin Pathway Agent (PPA) to Selexipag in SPHERE. J Hear Lung Transplant. 2019;38(4, Supplement):S486. doi:https://doi.org/10.1016/j.healun.2019.01.1236 REFERENCE #2: Parikh KS, Doerfler S, Shelburne N, et al. Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2020;75(4):299-304. doi:10.1097/FJC.0000000000000800 REFERENCE #3: Sargent T, Hansen L, Hohsfield R. Transitions between infused and oral prostacyclin pathway agents in pulmonary arterial hypertension: key considerations. Pulm Circ. 2020;10(3):2045894020931324. doi:10.1177/2045894020931324 DISCLOSURES: No relevant relationships by Brandon Budhram, source=Web Response No relevant relationships by Andrea Gardner, source=Web Response Speaker/Speaker's Bureau relationship with Janssen Please note: 2016-2021 Added 05/01/2021 by Nathan Hambly, source=Web Response, value=Honoraria Advisory Committee Member relationship with Janssen Please note: 2016-2021 Added 05/01/2021 by Nathan Hambly, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Honoraria Advisory Committee Member relationship with Boehringer Ingelheim Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Roche Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Roche Please note: 2016-2021 Added 04/30/2021 by Nathan Hambly, source=Web Response, value=Honoraria

Reasons for refusing parenteral therapy: a qualitative study of patients with pulmonary arterial hypertension

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.

Safety and Tolerability of a Rapid Transition From Intravenous Treprostinil to Oral Selexipag in Three Adolescent Patients With Pulmonary Arterial Hypertension.

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.

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study.

The association of autoimmune disease (AI) with transplant-free survival in the setting of severe Group 3 pulmonary hypertension and extensive pulmonary fibrosis remains unclear. We report cases of severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg and right ventricular dysfunction) and extensive pulmonary fibrosis after pulmonary arterial hypertension-specific therapy. We used multivariate regression to determine the clinical variables associated with transplant-free survival. Of 286 screened patients, 55 demonstrated severe pulmonary hypertension and extensive pulmonary fibrosis and were treated with parenteral prostacyclin therapy. The (+)AI subgroup (n = 34), when compared to the (–)AI subgroup (n = 21), was more likely to be female (77% versus 19%) and younger (58.7 ± 12.1 versus 66.0 ± 10.7 years), and revealed lower forced vital capacity (absolute) (1.9 ± 0.7 versus 2.9 ± 1.1 L), higher DLCO (% predicted) (31.1 ± 15.2 versus 23.2 ± 8.0), and increased unadjusted transplant-free survival (1 year (84.6 ± 6.3% versus 45 ± 11.1%)), 3 years (71 ± 8.2% versus 28.6 ± 11.9%), and 5 years (47.6 ± 9.6% versus 6.4 ± 8.2%); (p = 0.01)). Transplant-free survival was unchanged after adjusting for age and gender. The pulmonary hemodynamic profiles improved after parenteral prostacyclin therapy, independent of AI status. The baseline variables associated with mortality included age at pulmonary hypertension diagnosis (heart rate (HR) 1.23 (confidence interval (CI) 1.03–1.47); p = 0.02) and presence of AI (HR 0.26 (confidence interval (CI) 0.10–0.70); p < 0.01). Gas exchange was not adversely affected by parenteral prostacyclin therapy. In the setting of severe Group 3 pulmonary hypertension and extensive pulmonary fibrosis treated with pulmonary arterial hypertension-specific therapy, AI is independently associated with increased transplant-free survival. Pulmonary hypertension/pulmonary fibrosis associated with AI should be considered in future clinical trials of pulmonary arterial hypertension-specific therapy in Group 3 pulmonary hypertension.

Effects of Parenteral Prostacyclin Therapy on Echocardiographic Variables

<h3>Purpose</h3> To evaluate the effects of treating patients with pulmonary arterial hypertension (PAH) with parenteral prostacyclin (IV/SC PGI₂) therapy on echocardiographic parameters. <h3>Methods</h3> We retrospectively assessed echocardiograms of patients diagnosed with PAH by right heart catherization between 2007 and 2020. Patients were included if they had group 1 PAH with a baseline echocardiogram performed 0 - 12 months prior to starting PGI₂ therapy and follow up echocardiogram performed 3 - 18 months post therapy. Comparison between the two studies was done using paired Student t-tests or Wilcoxon signed rank tests, and categorical variables were reported as percentages. <h3>Results</h3> Out of 166 patients with PAH, 122 met study criteria. Mean age was 47 ± 13, 79% were female and IPAH/HPAH (52%) and CTD-PAH (32%) were the most common diagnoses. At baseline, severe right heart abnormalities were seen. Mean RVSP was 83 ± 21, and most patients had a moderately (33%) or severely (43%) dilated RA and a moderately (32%) or severely (40%) dilated RV. Echocardiogram was performed a mean 202 ± 105 days after IV/SC PGI2 therapy was initiated. Significant improvement in most echocardiographic parameters was seen, as shown in table 1. This included improvements in RVSP, RV size, RV function and tricuspid regurgitation severity. Of note, individuals with severely diminished RV function went down from 40% to 23% (p < 0.001), and patients with a severely dilated RV decreased from 55% to 23% (p < 0.001). Notably, however, there was no significant change in RA size, and while only 34% patients had a pericardial effusion at baseline, this increased to 44% (p = 0.047) at follow-up. In addition to the RV changes, LA size (p = 0.024) and LV diastolic diameter (p < 0.001) both increased. <h3>Conclusion</h3> Given the significant changes in key echocardiographic variables after prostacyclin therapy and the non-invasive nature of these studies, echocardiograms may be useful in monitoring patient responses to prostacyclin therapies.

The evolving treatment landscape of pulmonary arterial hypertension

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.

Pediatric subcutaneous treprostinil site maintenance and pain control strategies from the Pediatric Pulmonary Hypertension Network.

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.

PH Roundtable: Pulmonary Hypertension and Telehealth in the Time of Coronavirus Disease 2019

PH Roundtable: Pulmonary Hypertension and Telehealth in the Time of Coronavirus Disease 2019

Abstract 15193: Pulmonary Hypertension in Pregnancy: WHO Group 1 Outcomes Improved, Time to Focus on WHO Group 2

Introduction: Pregnancy is contraindicated in women with pulmonary hypertension (PH), yet many still decide to pursue pregnancy. Hypothesis: We hypothesized improved maternal mortality with PH at our center’s cardio-obstetrics program and sought to identify factors to estimate the risk of major adverse cardiac events (MACE). Methods: Pregnant women with right ventricular systolic pressure (RVSP) ≥35 mmHg or tricuspid regurgitant velocity &gt; 2.8 m/s on transthoracic echocardiogram (TTE) were identified. Women with intermediate to high probability PH by ESC criteria (TTE or catheterization, n = 70) were classified using the 6 th World Society of PH definitions. Results: In 70 women with PH (30 ± 6 years-old, RVSP 52 ± 16 mmHg) there were 12 (17%) with WHO Group 1 PH, 45 (64%) with Group 2 PH, 4 (6%) with Group 3 PH and 9 (13%) with Group 5 PH (Figure A). Baseline characteristics were similar except: Group 1 PH had 83% on prostacyclin (PC) therapy, higher RVSP (78 ± 20 mmHg vs. Groups 2 (46 ± 9), 3 (44 ± 2 mmHg) and 5 PH (48 ± 10mmHg), p&lt;0.01), and compared to Group 2 PH, more Group 1 PH women were diagnosed pre-pregnancy (9 (75%) vs. 12 (27%), p = 0.01) and had cardio-obstetrics care (10 (83%) vs. 16 (36%), p &lt; 0.01) (Figure B - E). There were no peripartum deaths, however 3 (4.3%) women with Group 2 PH had late mortality (7 ± 4 months post-partum). MACE occurred in 24 (34%) women and was more likely in those with: NYHA FC ≥ 2 (95% CI 4.7-57, p &lt; 0.01), pre-eclampsia (95% CI 1.2-13, p = 0.03), RVSP &gt;50 mmHg (95% CI 1.3-10, p = 0.02) and LVEF &lt;50% (95% CI 1.1-8.8, p = 0.04) (Figure F). Preterm birth occurred in 32 (49%) pregnancies, with no neonatal mortality. Conclusion: To conclude, in a large single center cohort we report 100% 1-year survival in Groups 1, 3, and 5 PH, with most Group 1 PH patients on PC therapy and under cardio-obstetrics care. We identify Group 2 PH as an under-recognized group for adverse outcomes in pregnancy, with NYHA FC, pre-eclampsia, RVSP &gt;50 mmHg and LVEF &lt;50% associated with increased MACE.

PREVALENCE AND OUTCOMES OF INHALED, ORAL, AND PARENTERAL PROSTACYCLIN THERAPY IN PULMONARY HYPERTENSION CLINIC PATIENTS: A RETROSPECTIVE COHORT STUDY

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Prostacyclin therapy has become a standard of current management for patients with severe pulmonary arterial hypertension (PAH). CurrentlY therapy may be administered via inhaled, oral, and parenteral routes, however there use is often reserved for patients with severe disease. This study aimed to assess the prevalence and effect via hemodynamic evaluation and functional outcome measurements of inhaled, oral, and parenteral prostacyclin therapy among pulmonary hypertension clinic patients. METHODS: This was a retrospective cohort study of pulmonary hypertension (PH) clinic patients at Keck Medical Center. Patients were studied from time of initial clinic visit and most recent follow up. Data ranged from 2011 to 2020. Patient demographics, hemodynamics via right heart catheterization (RHC), transthoracic echocardiography findings (TTE), and functional capacity via six-minute walk testing (6MWT) were collected. Patients were then separated by presence of prostacyclin therapy and route of administration if present. RESULTS: Data was collected on 473 PH patients, 298 of which had complete therapy data and were included in the final analysis. WHO group 1 PAH patients comprised 72% (n = 214) of all patients. The composition of prostacyclin therapy was as follows 152 (51%) no prostacyclin therapy (NP), 29 (9.7%) inhaled prostacyclin therapy (IP), 25 (8.3%) oral prostacyclin therapy (OP), 85 (28.5%) parenteral prostacyclin therapy (PP), and 7 (2.3%) combination therapy. Percentage of patients in each group with PAH was as follows NP (58.6%), IP (75.9%), OP (80%), PP (90.6%), and combination (85.7%). RHC hemodynamics revealed a significant relationship between increasing pulmonary artery pressures and pulmonary vascular resistance (PVR) and therapy in order from NP to IP to OP to PP at initial and follow up visit. TTE findings showed a significant relationship between increasing right ventricular (RV) dilation, RV dysfunction, RVSP, presence of pericardial effusion, and prostacyclin therapy from NP to IP to OP to PP. 6MWT revealed the PP group had the furthest distance walked and had an increase between at follow up while the IP group had the shortest 6MWT distance and greatest reduction in average 6MWT distance at follow up. CONCLUSIONS: The cohort of patients between types of therapy differed significantly in baseline characteristics and outcomes on cardiopulmonary hemodynamics and functional status. The PP group compared to IP and OP were shown to have more severe pulmonary hypertension. Despite that, they had greater 6MWT distances and even improved values from initial to follow up testing. The increase in distance adds to the body of literature suggesting the benefit of parenteral prostacyclin long term in comparison to other modes of drug delivery. CLINICAL IMPLICATIONS: This study may contribute to identifying subsets of patients with pulmonary hypertension who would benefit from prostacyclin therapy. DISCLOSURES: No relevant relationships by Tiffany Chang, source=Web Response No relevant relationships by Lucas Cruz, source=Web Response No relevant relationships by Jared Geibig, source=Web Response No relevant relationships by Moses Koo, source=Web Response No relevant relationships by Ashil Panchal, source=Web Response Speaker/Speaker's Bureau relationship with Actelion, United therapeutic, and Bayer Please note: $20001 - $100000 Added 05/30/2020 by Bassam Yaghmour, source=Web Response, value=Honoraria

CLINICAL IMPACT OF LIQ861 THROUGH ASSESSMENT BY THE CARDIOMEMS SYSTEM IN PULMONARY ARTERIAL HYPERTENSION: A CASE STUDY

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Prostacyclin therapy has established efficacy in pulmonary arterial hypertension (PAH) but is underutilized, in part due to challenges with dose uptitration and administration routes. LIQ861 (Liquidia Technologies) is an investigational, dry-powder formulation of treprostinil designed using PRINT® technology to enhance deep-lung drug deposition and delivery in 1-2 breaths per capsule, an improvement over current nebulized therapy. The INSPIRE trial (Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil) is a Phase 3, open-label, multicenter study to evaluate the long-term safety and tolerability of LIQ861 for PAH. METHODS: A 42-year-old female diagnosed with heritable PAH had an initial assessment of: 6-minute walk distance (6MWD), 339 m; N-terminal pro-brain natriuretic peptide (NT-proBNP), 2207 pg/ml; pulmonary artery pressure (PAP), 87/34 mm Hg; mean PAP (mPAP), 54 mm Hg; wedge pressure, 4 mm Hg; pulmonary vascular resistance, 14.7 Wood units (WU); total pulmonary resistance (TPR), 15.9 WU; and reduced cardiac index, 2.0 L/min/m2. Cardiac MRI revealed a severely dilated right ventricle (RV) and RV ejection fraction of 24%. Her REVEAL risk score (RRS) was 11. The patient refused parenteral prostacyclins and was initiated on tadalafil and ambrisentan. A CardioMEMS™ device was implanted. RESULTS: The patient improved on combination therapy over 24 months, with an RRS of 6; however, imaging showed a small pericardial effusion with a dilated, hypertrophied, and mildly dysfunctional RV with persistent evidence of pressure overloaded state. The patient enrolled in the INSPIRE trial. Baseline assessments for INSPIRE included: functional class (FC) II; 6MWD, 469 m; and NT-proBNP, 113 pg/ml. The starting LIQ861 dose was 26.5 mcg QID with an increase to 79.5 mcg QID after 3 weeks. By 3 months, the dose was uptitrated to 106 mcg QID. All pulmonary pressures as measured by the CardioMEMS™ device further declined within the first month of adding LIQ861. There were also increases in pulmonary vascular compliance, stroke volume index, and cardiac efficiency, and linear reductions in pulmonary vasculature elastance, RV power, RV stroke work, and TPR. Assessments at 4 months included improvement to FC I, increased 6MWD to 487 m, decreased NT-proBNP to 73 pg/ml, and decreased RRS to 3. RV size and function normalized, and evidence of RV pressure and pericardial effusion were no longer present. CardioMEMS™ readings demonstrated a completely normalized PAP of 32/12 mm Hg and mPAP of 20 mm Hg. CONCLUSIONS: This case illustrates an additive and favorable clinical, hemodynamic, and RV remodeling response to LIQ861 and the utility of the CardioMEMS™ system to monitor disease progression. CLINICAL IMPLICATIONS: The combination of CardioMEMS™-derived hemodynamic and adjunctive clinical information can inform clinical decisions regarding advancement in therapy and optimizing clinical status. DISCLOSURES: No relevant relationships by Raymond Benza, source=Web Response Consultant relationship with Fisher Paykel Please note: $5001 - $20000 by Nicholas Hill, source=Web Response, value=Grant/Research Support Consultant relationship with Philips Respiroics Please note: $1001 - $5000 by Nicholas Hill, source=Web Response, value=Consulting fee No relevant relationships by Manreet Kanwar, source=Web Response No relevant relationships by Soidjon Khodjaev, source=Web Response Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Consulting fee PI relationship with Actelion Please note: $20001 - $100000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Acceleron Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Consulting fee PI relationship with Acceleron Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support PI relationship with Bayer Please note: $20001 - $100000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support Scientific Medical Advisor relationship with Gilead Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Honoraria PI relationship with Complexa Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Liquidia Please note: $1001 - $5000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Consulting fee PI relationship with Liquidia Please note: $20001 - $100000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support PI relationship with PhaseBio Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support Consultant relationship with Respira Please note: $1001 - $5000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Consulting fee Adjudecation committee member relationship with Pfizer Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Honoraria Advisory Committee Member relationship with United Therapeutics Please note: $5001 - $20000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Honoraria PI relationship with United Therapeutics Please note: $20001 - $100000 Added 04/09/2020 by Ioana Preston, source=Web Response, value=Grant/Research Support

Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension.

The combination of bosentan and sildenafil is commonly used to treat patients with pulmonary arterial hypertension (PAH); however, there is evidence of a significant drug interaction between these two medications. We sought to evaluate the safety and efficacy of transitioning patients with PAH from the combination of bosentan and sildenafil to alternative therapy. A retrospective database review was performed on 16 patients with PAH who were treated with the combination of bosentan and sildenafil and transitioned to alternative treatment at our center. Invasive and non-invasive patient parameters were collected at baseline and after transition. 56.3% of patients were in World Health Organization functional class (WHO FC) III and a majority of patients (68.7%) were on background prostacyclin therapy. The most common reason for transition was concern for a drug interaction in seven patients (43.8%). The most common transition was bosentan to macitentan in eight patients (50%). Fifteen patients (93.8%) tolerated the transition after a median follow-up of 6.5 months with minor adverse events occurring in four patients (25%). In 11 patients, 6-min walk distance (6MWD) was unchanged comparing baseline to post transition measurements with a median change of +8 m (range: −50 to + 70; P = 0.39). Nine patients (81.8%) had stable (within 15% margin) or significant improvement (increase by ≥15%) in 6MWD after transition. All patients demonstrated stable or improved WHO FC after transition. There were no significant changes after transition in hemodynamics, N-terminal pro-brain natriuretic peptide (NT-proBNP) values, or Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk scores. In our study, transitioning patients from bosentan and sildenafil to alternative therapy was safe and resulted in clinical stability.

TRANSITIONING FROM TYVASO TO LIQ861 IN PULMONARY ARTERIAL HYPERTENSION: A CASE STUDY

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: LIQ861 (Liquidia Technologies) is an investigational, dry-powder formulation of treprostinil designed using PRINT® technology to enhance deep-lung drug deposition and achieve higher dose levels over current nebulized prostacyclin therapies for pulmonary arterial hypertension (PAH) in 1-2 breaths per capsule. INSPIRE (Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil) is a Phase 3, open-label, multicenter study of the long-term safety and tolerability of LIQ861. This case evaluates the clinical impact of transitioning treprostinil administration from a Tyvaso® nebulized device to LIQ861 with a dry-powder inhaler. METHODS: A 42-year-old male with ALK1 mutation PAH (functional class [FC] II) and hereditary hemorrhagic telangiectasia was referred to a PAH comprehensive care center for evaluation. Diagnostic hemodynamics were consistent with precapillary PAH. The patient did not tolerate sildenafil or tadalafil due to worsening nosebleeds or macitentan due to fluid retention, and could only tolerate inhaled treprostinil using a Tyvaso® device. He initially titrated to 6 breaths QID but then decreased to 3 breaths QID due to worsening cough. He remained stable in FC II, with an N-terminal pro-brain natriuretic peptide (NT-proBNP) of 30 pg/ml and a 6-minute walk distance (6MWD) of 542 m with no desaturation. He was considered stable to enroll in the INSPIRE study. Assessments at baseline included pulmonary artery pressure of 71/34 mm Hg, mean pulmonary artery pressure of 46 mm Hg, wedge pressure of 13 mm Hg, and pulmonary vascular resistance of 4.6 Wood units. The ESC/ERS risk score was assessed as low with a 6MWD of 558 m, FC II, and NT-proBNP of 62 pg/ml. The total score of the Minnesota Living with Heart Failure Quality of Life (MLWHF) questionnaire was 70. RESULTS: The patient initiated LIQ861 at 26.5 mcg QID. The dose was increased to 53 mcg QID after 4 weeks but reduced to 26.5 mcg QID after 1 week due to worsening cough. An increase to 53 mcg QID was attempted again at Week 8 but immediately decreased to 26.5 mcg QID due to severe cough and desaturation while on oxygen. The dose remained stable at 26.5 mcg QID through Month 12 with no notable adverse events. Assessments at Month 12 showed a risk score maintained as low, including FC II, a 6MWD of 569 m, and NT-proBNP of 124 pg/ml. The MLWHF total score was stable at 69. The patient remained stable on the same dose throughout the duration of the study (2 months), continued to tolerate the same dose a year later, and maintained his low ESC/ERS risk status. CONCLUSIONS: Transition from monotherapy with Tyvaso® to LIQ861 in this patient was well-tolerated and the patient remained stable during the study. CLINICAL IMPLICATIONS: In low-risk PAH patients monotherapy with inhaled prostacyclin LIQ861 is well-tolerated and maintains clinical status. DISCLOSURES: Speaker relationship with Actelion Please note: $5001 - $20000 by Sandeep Sahay, source=Web Response, value=honoraria Speaker relationship with United Therapeutics Please note: $5001 - $20000 by Sandeep Sahay, source=Web Response, value=honoraria speaker relationship with Bayer Please note: $5001 - $20000 by Sandeep Sahay, source=Web Response, value=honoraria My spouse/partner as a Speaker relationship with BTG Please note: $5001 - $20000 by Sandeep Sahay, source=Web Response, value=honoraria brief interview relationship with Liquidia Technologies Please note: $1-$1000 Added 05/26/2020 by Sandeep Sahay, source=Web Response, value=Honoraria

OVERUSE OF AEROSOLIZED PROSTACYCLIN IN THE MANAGEMENT OF ARDS

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Prone ventilation is often under-utilized in the management of acute respiratory distress syndrome (ARDS). One potential reason could be due to use of aerosolized prostacyclin which is known to improve the oxygenation status. As a result of improved oxygenation, clinicians may delay other treatment modalities such as proning which has been associated with both improved oxygenation and mortality. Therefore, we aimed to look at our institutions’ use of aerosolized prostacyclin in patients who might be eligible for proning instead. METHODS: We performed a retrospective chart review of patients admitted to the medical intensive care unit (MICU) between 2016 and 2018 for ARDS using the Berlin definition. We enrolled patients only if they were on mechanical ventilation for = 48 hours. We collected the following data: age, gender, body mass index (BMI), PaO2/FiO2 (P/F) ratios on days 1-3, comorbidities, aerosolized prostacyclin use and adjunctive therapies (proning, neuromuscular blockade). We defined patients with BMI = 36 kg/m2 and P/F = 150 as those eligible for proning. RESULTS: Eighty six patients with ARDS were identified of which 41 (48%) received aerosolized prostacyclin. On day 1, twenty four patients had P/F = 150. Amongst this group, 13 (54%) patients eligible for proning continued to receive prostacyclin instead. On day 2, four (31%) out of the 13 patients had P/F = 150 but were not proned. Overall, aerosolized prostacyclin was used in 52% of patients in 2016, 65% of patients in 2017 and 30% of patients in 2018. CONCLUSIONS: We found that aerosolized prostacyclin was administered frequently in managing patients with severe ARDS and proning was under-utilized. This could be due to three reasons: transient improvement in oxygenation after starting prostacyclin therapy thus discouraging the clinician to consider proning, patient’s body habitus and the laborious nature of prone positioning. The reduction in prostacyclin over the 3-year study period use could be due to increased awareness of adjunctive measures for ARDS. Our study did not account for contraindications to proning such as spinal instability, unstable fractures, burns and high intra-cranial pressure; however, at our institution such patients are admitted to the surgical ICU. The major limitations of our study are its small sample size and retrospective methodology. Therefore, the generalizability is limited. In summary, aerosolized prostacyclin use in ARDS treatment continues to remain high. CLINICAL IMPLICATIONS: Overuse of nebulized prostacyclin may lead to under utilization of proning due to the transient improvement of hypoxemia seen with prostacyclin use in the management of ARDS. DISCLOSURES: No relevant relationships by Ryan Hyde, source=Web Response No relevant relationships by Johnny Jaber, source=Web Response No relevant relationships by Saminder Kalra, source=Web Response No relevant relationships by Sarina Parikh, source=Web Response No relevant relationships by Raju Reddy, source=Web Response No relevant relationships by Daniel Urbine, source=Web Response

BLOODSHED TREATED SUCCESSFULLY IN A HOUSE OF VILLAINS: A CHALLENGING AND UNUSUAL CASE OF HEMOPTYSIS IN A PATIENT WITH CONNECTIVE TISSUE DISEASE- PULMONARY ARTERIAL HYPERTENSION

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive disease caused by a remodeling of precapillary arterioles that leads to a progressive increase in pulmonary vascular resistance and right ventricular failure. PAH can complicate any connective tissue disease, most frequently SSc as discussed above, but also SLE, MCTD, RA, or other diseases such as Sjogren’s syndrome (SS) and dermatomysositis with often a poor prognosis. Our case illustrates a case of Hemoptysis under uniquely complex circumstances. CASE PRESENTATION: 53-year-old Hispanic female initially presented with features of severe Acute right heart failure, cardiogenic shock and Hypoxemia. Pulmonary arterial hypertension (PAH) diagnosis was made and was stabilized on emergent parenteral prostacyclin therapy. We also found connective tissue disease (CTD) with Sjogren’s features. She had history of recurrent Venous thromboembolism (VTE) and was on rivaroxaban. PAH therapy - SQ Treprostinil (@ 60ng/kg/min) + tadalafil 40mg qd. A few months later, she developed (CNPA). She responded well to voriconazole with clinical & radiographic improvement. A significant cutaneous allergic reaction to voriconazole led to its cessation and substitution with posaconazole. She presented with large volume hemoptysis with preceding minor episodes for several days. She was hemodynamically stable with no constitutional symptoms. CT chest revealed a stable appearing right upper lobe pulmonary mass measuring 5.5 x 3.0 cm. BNP was 67. Anticoagulation was held and an IVC filter was placed emergently. Bronchoscopy revealed necrotic debris, tan purulent mucous, and blood in the anterior segment of the right upper lobe. Interventional radiology performed bronchial and subclavian angiography with chemoembolization (small branch of the right subclavian artery & the distal portion of the right bronchial artery) of the Aspergilloma. Anticoagulation was resumed after with no further episodes of hemoptysis and she was successfully discharged. DISCUSSION: In a review of patients with SS & PAH, the mean age at diagnosis of PAH was 50 and all female with severe functional class (FC III and IV) and hemodynamic impairment (1), strikingly similar to our case. Survival rate was low (66% at 3 years) as standard therapy of PAH was typically ineffective despite an initial improvement. However, Significant clinical improvement was noted in our patient with Parenteral prostacyclin therapy and PDE5 inhibitors. CONCLUSIONS: This case illustrates a complex unique clinical situation that was challenging – Hemoptysis from CNPA with a background of the following active diagnoses: PAH, CTD (Sjogren’s features), Recurrent VTE. Chemoembolization of feeding arteries + IVC filter placement + temporary cessation of anticoagulation was used with a successful outcome. Reference #1: Sato T, Hatano M, Iwasaki Y, et al. Prevalence of primary Sjögren's syndrome in patients undergoing evaluation for pulmonary arterial hypertension. PLoS One. 2018;13(5):e0197297. Published 2018 May 15. doi:10.1371/journal.pone.0197297 DISCLOSURES: Clinical Research - PI relationship with United Therapeutics Please note: 3 years Added 05/08/2020 by Vijay Balasubramanian, source=Web Response, value=Grant/Research Support Speaker relationship with Bayer Please note: 3 years Added 05/08/2020 by Vijay Balasubramanian, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $1001 - $5000 Added 05/08/2020 by Vijay Balasubramanian, source=Web Response, value=Honoraria No relevant relationships by Eric Reid, source=Web Response No relevant relationships by James Yang, source=Web Response

Prognostic Value of Change in Cardiac Index After Prostacyclin Initiation in Pediatric Pulmonary Hypertension

Invasive hemodynamic assessment remains the gold standard for the diagnosis of pediatric pulmonary hypertension and for longitudinal assessment of response to therapy. This analysis sought to describe the changes in hemodynamic variables after initiation of prostacyclin therapy and determine which changes bear predictive power of adverse clinical outcomes. A retrospective chart review of established patients at Cincinnati Children's Hospital with pulmonary arterial hypertension (PAH) who required prostacyclin therapy between 2004 and 2018 was performed. The baseline hemodynamic parameters at diagnosis as well as change in those parameters between initial catheterization and post-prostacyclin initiation catheterization were independent variables. Cox proportional hazard regression and recursive partitioning analysis were used to characterize which hemodynamic factors predicted the composite adverse outcome (CAO) defined as death, lung transplantation, or reverse Pott's shunt surgery. During the study period, 29 patients met inclusion criteria in which there were 7 CAOs: 4 deaths, 3 lung transplants, and 2 reverse Pott's shunts. Median time between catheterizations was 86days and between the initiation of prostacyclin therapy and the second catheterization was 54days. Cox regression revealed that only baseline pulmonary artery pressure (> 51mmHg) and a failure to increase cardiac index illustrated statistically significant hazard for occurrence of the CAO (p < 0.01). These criteria significantly dichotomized the population in a Kaplan-Meier analysis into likelihoods of experiencing the CAO. While controlling for other hemodynamic variables, the absence of augmentation of cardiac index after the initiation of prostacyclin therapy is a valuable prognostic indicator of adverse PAH outcomes in pediatrics.

Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival.

Background:Insulin like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH.Methods:Serum was analyzed by ELISA for IGF1, and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n=175), and a cohort of asthmatic subjects (n=46, age 0-21) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic, and clinical variables for PAH severity.Results:Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output, and 6 minute-walk-distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p<0.001.), but not IGF1 (p=0.13).Conclusion:Circulating IGFBP2 is a novel marker for pediatric PAH which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension.