BACKGROUND:For patients with acute pulmonary embolism (PE), assessment of prognosis helps with risk stratification, triage for level of care, management strategy, and communication among healthcare workers and patients. We sought to identify prognostic models and individual factors associated with short-term outcomes after acute symptomatic PE. METHODS:We performed a systematic review of prognostic factors for PE, searching MEDLINE, Embase, and Web of Science for records up to 1 June 2024. Studies of any design evaluating potential prognostic models or individual variables (not contained in the models) associated with short-term mortality after acute PE were included. RESULTS:We identified 314 studies that included 2,495,115 patients. Of these, 225 studies included 2,267,952 patients and evaluated 24 prognostic models for patients with acute PE. The most frequently used validated models were the simplified Pulmonary Embolism Severity Index (sPESI) (127 studies), the original PESI (79 studies), and the European Society of Cardiology risk schema (34 studies). Each model-development study had a c-index ≥ 0.7. Individual factors associated with prognosis included older age, presence of coexisting conditions, abnormal clinical signs and symptoms, clot burden, markers of right‑ventricle dilatation/dysfunction and myocardial injury, altered laboratory results indicating impaired haemodynamics, and tests that assess for systemic inflammation. Pooled odds ratios for variables not contained in any eligible prognostic model ranged from 1.43 (for D-dimer) to 2.65 (for right heart thrombi). CONCLUSIONS:This systematic review identified 24 prognostic models and 18 individual variables distinct from the prognostic models associated with short-term mortality after acute PE.

Background: Bronchopulmonary dysplasia (BPD) and prolonged invasive mechanical ventilation in preterm infants are associated with an increased risk for respiratory morbidity and adverse neurodevelopmental (ND) outcomes in early childhood. The use of nasal CPAP has been shown to reduce the duration of mechanical ventilation and risk for BPD. Bubble CPAP has physiologic properties that decrease lung injury, which may lead to better respiratory and developmental outcomes through prevention of BPD. To date, there is no study that reports the ND and health outcomes of infants treated with bubble CPAP. Methods: One hundred twenty infants treated with bubble CPAP were compared with 114 infants treated with infant flow driver (IFD) CPAP. Outcomes included Bayley-III scores, hospitalizations, emergency department visits, subspecialists, and therapies through the age of 2 years. Multiple regression analyses adjusted for effects of social and neonatal risk factors on outcomes. Results: Infants in the bubble CPAP group had lower rates of intubation (P = .02), need for surfactant administration (P < .001), and noninvasive ventilation (P < .001) as compared with infants treated with IFD CPAP. In extremely low birthweight infants (<1,000 g), treatment with bubble CPAP was predictive of higher cognitive scores at 20 months corrected age (CA) (P = .02). Conclusions: Use of bubble CPAP was associated with higher cognitive scores at 20 months CA in extremely low birthweight infants but not for infants with birthweight >1,000 g.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of acute pulmonary embolism (PE), affecting approximately 2.7% of PE survivors. CTEPH results from persistent obstruction of the proximal pulmonary arteries by organized fibrotic clots, in combination with a secondary microvasculopathy, leading to increased pulmonary vascular resistance and progressive right heart failure. The mechanisms precluding a complete resolution of PE are not yet fully understood and include chronic inflammation, impaired fibrinolysis and coagulation abnormalities. Chronic thromboembolic pulmonary disease is the broader term for symptomatic patients with mismatched perfusion defects and signs of chronic thrombi on pulmonary vascular imaging, after at least 3 months of therapeutic anticoagulation, with CTEPH specifically referring to those with pulmonary hypertension. In patients with persistent dyspnea after PE or with PH, the diagnosis of CTEPH is suspected when ventilation/perfusion lung scan shows mismatched perfusion defects and is confirmed by comprehensive right heart catheterization and imaging with CT pulmonary angiography and/or digital subtraction angiography, which ought to be performed at centers with CTEPH expertise. Indeed, early referral to expert centers with experienced multidisciplinary teams ensures accurate diagnosis and tailored treatment, ultimately improving outcomes for CTEPH patients.

Pregnancy in patients with pulmonary arterial hypertension (PAH) is a high-risk condition associated with high morbidity and mortality. Patients with severe PAH are often advised against pregnancy. Still, those patients who pursue pregnancy require a dedicated and multidisciplinary approach since the progression of fetal growth will accompany significant hemodynamic changes, which can be challenging for patients with a poorly functioning right ventricle. In this article, we describe the approach to the unique cardiovascular, respiratory, hematologic, and social challenges that pregnant patients with PAH face throughout pregnancy. We discuss the impact of these physiologic changes on diagnostic studies commonly used in PAH and how to incorporate diagnostic data in making the diagnosis and risk stratifying pregnant patients with PAH. The pharmacologic challenges of pulmonary vasodilators in pregnancy are discussed as well. Pregnant patients with PAH are at particularly high risk of mortality around the time of delivery, and we discuss the multidisciplinary approach to the management of these patients, including the use of anesthesia, inotropic support, type of delivery, and postpartum care, providing clinicians with a practical approach to the management of this difficult condition.

Background:Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown. Methods:We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC. Results:During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular. Conclusions:We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC.

Background Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. Methods Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus >= 4 WU and <5 WU versus >= 5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. Results Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs( -1)0.3 m). Patients with a PVR of <= 5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. Conclusion Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

BACKGROUND:This meta-analysis aims to investigate the safety and efficacy of catheter-directed thrombectomy (CDT) without using adjunct thrombolysis as reperfusion therapy to manage intermediate and high-risk pulmonary embolism (PE). METHODS:A literature search of Ovid MEDLINE, Embase, CiNAHL, Cochrane Library, and Web of Science was conducted from inception to January 2024. Eligible studies reported more than 10 patients treated for acute PE with catheter-directed thrombectomy only, who were over 18 years of age. Primary endpoints were major bleeding, in-hospital mortality, and hemodynamic changes. RESULTS:Eighteen studies (n = 803) were included for quantitative analysis. The pooled estimate of incidences of in-hospital mortality and major bleeding was 1.8 % (95 % CI 0.009, 0.027) and 2.1 % (95 % CI 0.011, 0.031) respectively. A pooled estimate reported a post-procedural increase in oxygen saturation and systolic blood pressure by 8.96 % (95 % CI: 3.54, 14.38) and 15.02 mmHg (95 % CI 6.35, 23.69) respectively. Post-procedural mean pulmonary artery pressure, right ventricle/left ventricle (RV/LV) ratio, and Miller score were reduced by 10.30 mmHg (95 % CI -14.94, -5.66), 0.29 (95 % CI -0.50, -0.08) and 8.09 (95 % CI -10.70, -5.47) respectively. CONCLUSION:CDT without adjunctive thrombolysis may lead to improvements in hemodynamic outcomes and exhibits favorable safety profiles. This meta-analysis provides a rationale for lowering the threshold for considering this technique, and ongoing randomized trials will further advance the field to determine optimal managment strategies for intermediate and high-risk acute PE.

BACKGROUND:Mortality risk assessment informs clinical management of pulmonary arterial hypertension (PAH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 is a simplified risk calculator discriminating 1-year mortality risk. METHODS:This post-hoc analysis of the phase 3 GRIPHON study assessed changes in REVEAL Lite 2 risk score with selexipag versus placebo and whether changes were prognostic or predictive of time to first morbidity/mortality (M/M) event. RESULTS:REVEAL Lite 2 risk category discriminated M/M risk (landmark concordance indices: 0.68-0.76, selexipag; 0.65-0.70, placebo). Across baseline risk categories, hazard ratios supported a lower risk of M/M events with selexipag versus placebo: low, 0.573 (95% confidence interval [CI] 0.361-0.908; p = 0.0178); intermediate, 0.423 (95% CI 0.274-0.655; p = 0.0001); and high, 0.711 (9% CI 0.520-0.972; p = 0.0326). Odds ratios for risk improvement were 2.0 (95% CI 1.50-2.65), 1.8 (95% CI 1.38-2.43), and 2.0 (95% CI 1.43-2.72) for selexipag versus placebo at 16, 26, and 52 weeks, respectively (all p < 0.001). REVEAL Lite 2 risk improvement at week 16 explained 19.1% of the treatment effect in all patients and 47.0% in patients with REVEAL Lite 2 baseline risk score of ≥7. CONCLUSIONS:REVEAL Lite 2 can monitor PAH M/M risk and facilitate treatment optimization. Baseline REVEAL Lite 2 risk score was prognostic of M/M risk in patients with PAH and mediates treatment effect up to 47% for those at higher risk. Lower M/M risk with selexipag versus placebo occurred irrespective of baseline risk category (ClinicalTrials.gov identifier: NCT01106014).

Background Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study ( ClinicalTrials.gov : NCT03496623 ) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. Methods Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. Results In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. Conclusions The risk–benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

The PERFECT study, a randomized, controlled, double-blind study of inhaled treprostinil in patients with COPD and associated pulmonary hypertension (PH-COPD) was a negative trial that was terminated early. The reason(s) for the negative outcome remains uncertain. A post hoc analysis of data from the PERFECT study was undertaken to identify adverse responders and possibly potential responders. The goal was also to provide insight into phenotypes for possible inclusion and exclusion in future PH-COPD clinical trials. An adverse response on active treatment was seen in 36.4% (24/66) of the subjects compared to 27.6% (16/58) on placebo. There was no evidence to suggest that hyperinflation, bronchospasm, or occult heart failure played any role in the untoward outcomes of the study. The patients who died during the study all had baseline diffusing capacity for carbon monoxide ≤25% of predicted. Evidence of a potential response was seen in 10.6% (7/66) of the patients who received inhaled treprostinil. Patients who had evidence of a treatment response had a baseline mean pulmonary artery pressure of ≥40 mmHg and a forced expiratory volume in the first second of ≥40%. Change in N-terminal prohormone of brain natriuretic peptide did not predict clinical response. This post hoc analysis provides information that may potentially enable improved selection of patients for future therapeutic trials in PH-COPD. These analyses are post hoc, observational, and exploratory. The thresholds defining the spectrum of responders are preliminary and may require further refinement and validation in future studies.

Background Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined. Methods We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots. Results US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

PURPOSE:This study investigated physician compliance with indications for inferior vena cava (IVC) filter placement according to the 2012 American College of Chest Physicians (ACCP) and the 2011 Society of Interventional Radiology (SIR) guidelines. MATERIALS AND METHODS:A retrospective medical record review of 231 retrievable IVC filters placed between August 15, 2016, and December 28, 2017, at a large urban academic medical center. Guideline compliance to the 2012 ACCP and the 2011 SIR guidelines, and indications for IVC filter placements were assessed through an adjudication protocol. Filter retrieval and complication rates were also examined. RESULTS:Compliance to guidelines was low (60.2% for ACCP; 74.0% for SIR), especially for non-intensive care unit (ICU) patients (ICU 74.6% vs non-ICU 54.8%, p=0.007 for ACCP; ICU 82.5% vs non-ICU 70.8%, p=0.092 for SIR). After adjudication, 8.2% (19/231) of filters were considered non-indicated but reasonable, 17.7% (41/231) non-indicated and unreasonable, and 13.9% (32/231) SIR-indicated but not ACCP-indicated. The most common indication was venous thromboembolism with contraindication to anticoagulation. The most common reasons for non-compliance were distal deep venous thrombosis with contraindication to anticoagulation (19/60, 31.6%) and clot burden (19/60, 31.6%). One-year filter retrieval and 90-day complication rates were 32.0% (74/231) and 6.1% (14/231), respectively. CONCLUSION:Compliance to established guidelines was low. Reasons for non-compliance included limitations or discrepancies in guidelines, as well as non-evidence-based filter placements.Clinical ImpactDespite increasing utilization of inferior vena cava (IVC) filters, guideline compliance for IVC filter placement among providers is unclear. The results of this study indicate that physician compliance to established guidelines is poor, especially in non-intensive-care-unit patients. Noncompliance stems from non-evidence-based filter placement as well as differences and limitations in guidelines. Avoiding non-indicated IVC filter placement and consolidation of guidelines may significantly improve guideline compliance. The critical insights gained from this study can help promote judicious use of IVC filters and highlight the role of venous thromboembolism experts in navigating complex cases and nuances of guidelines.

BackgroundThe understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period.MethodsWe conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection.ResultsWe identified three phenotypic clusters associated with PASC that could be characterized as remittent, persistent, or incident based on the 3-month change in symptom number compared to study entry: remittent (median; min, max: −4; −17, 3), persistent (−2; −14, 7), or incident (4.5; −5, 17) (p = 0.041 remittent vs. persistent, p < 0.001 remittent vs. incident, p < 0.001 persistent vs. incident). Despite younger age and lower hospitalization rates, the incident phenotype had a greater number of symptoms (15; 8, 24) and a higher proportion of participants with PASC (63.2%) than the persistent (6; 2, 9 and 52.2%) or remittent clusters (1; 0, 6 and 18.7%). Systemic corticosteroid administration during acute infection was also associated with PASC at 3 months [OR (95% CI): 2.23 (1.14, 4.36)].ConclusionAn incident disease phenotype characterized by symptoms that were absent during acute illness and the observed association with high dose steroids during acute illness have potential critical implications for preventing PASC.

Introduction: Pulmonary embolism (PE) is a common and significant source of mortality and morbidity world-wide. A subset of patients with PE, particularly those who have intermediate and high risk events, are at increased risk for long-term right ventricular (RV) dysfunction; however, the impact of novel advanced therapies used for acute PE, including catheter-directed intervention, on long-term RV function remains uncertain. We sought to determine whether use of advanced therapies (catheter-directed intervention or systemic thrombolysis) is associated with improved long-term RV function. Materials and methods: Retrospective, single-center cohort study of adult (>= 18 year old) patients admitted and discharged alive with a diagnosis of acute PE, who fell under the category of intermediate or high risk, with available follow-up echocardiograms at least 6 months after the index, seen at a single quaternary referral center in Los Angeles, CA between 2012 and 2021. Results: There were 113 patients in this study (58 (51.3 %) treated with anticoagulation alone, 12 (10.6 %) treated with systemic thrombolysis, and 43 (38.1 %) treated with catheter-directed intervention), with approximately equal gender and racial distribution. Patients treated with advanced therapies were significantly more likely to have moderate-severe RV dysfunction (100 % for those treated with thrombolysis, 88.3 % for those treated with catheter-directed intervention, vs 55.2 % for those treated with anticoagulation alone; p < 0.001). At a follow-up of about 1.5 years, patients treated with advanced therapy (systemic thrombolysis or catheter-directed intervention) were more likely to have normalization of RV function (93-100 % vs 81 % for anti-coagulation alone, p = 0.04). The subgroup of patients with intermediate-risk PE was significantly more likely to have normalization of RV function (95.6 % vs 80.4 % for anticoagulation alone, p = 0.03). Use of advanced therapy was not associated with substantial short-term adverse events among patients who survived to hospital discharge. Conclusion: Patients with intermediate and high risk PE were more likely to have recovery in RV function long-term if treated with catheter-directed intervention or systemic thrombolysis, as compared to anticoagulation alone, without substantial safety issues, despite having worse RV function at baseline. Further data is needed to verify this observation.

Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes. Post hoc analyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefit versus initial double combination on haemodynamic and functional parameters in TRITON. Post hoc analyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6 months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7 days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52% versus control (HR: 0.48; 95% CI: 0.35–0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46–1.10) for the pooled selexipag versus control group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. These post hoc, pooled analyses build on previous insights, further supporting selexipag use within 6 months of diagnosis, including as part of triple therapy, to delay disease progression.

Background Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodelling and plexiform lesions. Cardiosphere-derived cells (CDCs) are heart-derived progenitor cells exhibiting anti-inflammatory and immunomodulatory effects, are anti -fibrotic, anti-oxidative and anti-apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation. Methods The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I) PAH, Heritable (H) HPAH, PAH-connective tissue disease (CTD) and PAH-human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n = 6). Phase 1b was a doubleblind placebo-controlled study (n = 20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year. Findings No short -term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 h monitored in hospital. There were no long-term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long-term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favouring CDCs (n = 16) compared to placebo (n = 10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6 -min walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favouring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long-term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12-months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long-term follow up through 12 months. Interpretation Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease -modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDC's potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm.

IntroductionThe 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD.MethodsOf 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded.ResultsAt INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and −19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL−1at RCT baseline to 359 pg·mL−1at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinilversusplacebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49–0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients.ConclusionsThese results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.