Objectives Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH.Methods We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes.Results This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively).Conclusions Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

Patients with pulmonary hypertension (PH) have been among those affected heavily by the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Early case series reported case fatality rates ranging from 19–45% in small series of 11–70 patients with PH who contracted COVID-19 [1–4]. A prospective series of 211 French patients with various forms of PH, who developed COVID-19 between February 2020 and April 2021, found an overall case fatality rate of 24.6% [5]. In patients with pulmonary hypertension, the mortality rate associated with COVID-19 has declined sharply with the emergence of the Omicron variants https://bit.ly/42OMsfj

Introduction. Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension characterized by obstruction of the pulmonary arteries by organized thrombi. Secondary hypoxia-mediated bronchoconstriction could be the cause of an obstructive ventilatory defect, while pulmonary infarction or right heart failure could be correlated with a restrictive ventilatory defect. Low diffusion capacity of the lungs for carbon monoxide (DLCO) level is the consequences of microvasculopathy. Aim. The aim of the study was to investigate the pattern of lung function impairment in patients suffer from CTEPH. Methods. The study was designed as a descriptive study. The study included patients with confirmed CTEPH without obstructive or restrictive lung diseases. Pulmonary function tests (PFTs) were performed and interpreted according to ATS/ERS guidelines from 2005. PFTs were performed in the stable phase of the disease. Results. The study included 60 patients (mean age 76.13 ± 2.16 years, 60% female) over a three-year period, from January 2019 to December 2021. Obstructive ventilatory defect was registered in 4 patients, 6.66% (FEV1/FVC 67.82 ± 2.15), restrictive ventilatory defect in 17 patients, 28.33% (TLC 3.92 ± 0.54 l, 68.5 ± 2.21% pred.), mixed ventilatory defect was not registered. All patients had a reduced DLCO values (3.73 ± 1.28 mmol/min/kPa, 48.87 ± 15.32% pred.), where the Krogh9s constant was 0.91 ± 0.23 mmol/min/kPa/l, 70.27 ± 16.32% pred. Conclusions. The pattern of lung function impairment with restrictive ventilatory defect and reduced DLCO values indicates a differential diagnosis of CTEPH in patients without other lung diseases.

BACKGROUND:Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients.METHODS:We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension).FINDINGS:The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries).INTERPRETATION:A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration.FUNDING:COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

BACKGROUND:A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS:We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS:The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS:Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities.

BACKGROUND: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. METHODS: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. RESULTS: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by >= 35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. CONCLUSION: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials. (C) 2022 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.

BACKGROUND:Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data.METHODS:The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD.RESULTS:A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of follow-up, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of "Non-Eisenmenger PAH" patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described.CONCLUSIONS:Analyzing "real life data" from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the "Non-Eisenmenger PAH" group and to patients with complex CHD, including Fontan patients.TRIAL REGISTRATION:www.clinicaltrials.gov, study identifier: Clinicaltrials.gov NCT01347216.

Introduction: In the last five years, there has been a growing trend towards the use of direct oral anticoagulants (DOACs) as a long-term anticoagulant therapy in patients who have had pulmonary embolism (PE). Vitamin K antagonists (VKAs) still remain the first-line anticoagulant therapy. Aim: The aim of the study was to investigate the type of long-term anticoagulant therapy after PE as a risk factor for the severity of chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Ordinal logistic regression was used to examine the effect of therapy on the severity of CTEPH. The severity of CTEPH was defined according to the values of parameters measured by right heart catheterization. Results: CTEPH was diagnosed in 21 patients over a two-year period. A higher proportion of patients had therapy with DOACs versus VKA, 71.4% vs. 28.6%. According to the mean pulmonary arterial pressure (mPAP) value, the largest number of patients had the severe form of the disease, followed by moderate and mild forms, 42.9% vs. 33.3% vs. 23.8% respectively. The choice of anticoagulants did not show any statistically significant effect on any of the parameters regarding the severity of CTEPH (Table 1). Conclusions: The type of anticoagulant therapy in patients with CTEPH is not associated with any hemodynamic parameters and does not affect the severity of the disease.

Background Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk. Methods We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models. Results Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four -stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk. Conclusions Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.

Pulmonary endarterectomy (PEA) is the recommended treatment for operable chronic thromboembolic pulmonary hypertension (CTEPH). We investigated survival according to operability in medically treated CTEPH patients included in the COMPERA registry. 639 newly diagnosed patients started with specific PH therapy had at least 1 follow-up (FU) visit. At inclusion, 281 (44%) were inoperable due to peripheral disease (SurgInop) and 89 (14%) due to comorbidities (MedInop); 70 (11%) had surgically accessible disease (ACC); 76 (12%) refused PEA (RefPEA); and 31 (4%) had residual pulmonary hypertension after surgery (PostPEA). Of these patients, 71 (11%) underwent PEA during FU, representing 11, 4, 30, 4, and 3 % of the respective subgroups. Mean age increased from operated at FU (61 y) to SurgInop (68 y), MedInop (72 y), and RefPEA (75 y). More females had ACC and more males RefPEA. Functional class was lower in PostPEA patients. Six min walking distance was highest PostPEA (376±108 m) and lowest in MedInop patients (266±115), while PVR was lowest in PostPEA (624±291) and highest in RefPEA (801±385 dsc-5). MedInop patients had significantly worse 5-year survival (37%, p<0.023) than other subgroups. Patients operated during FU had better survival than RefPEA patients (83 vs 63%, p=0.015). Operable RefPEA patients had a similar survival rate to SurgInop patients (62%). The main cause of death was right heart failure in all subgroups (33-67%) except in patients operated during FU (17%) who died mostly from bleeding, respiratory and multiorgan failure. In conclusion, despite the use of medical therapy, survival is still better in operated patients. Refusing PEA is prognostically as unfavourable as being SurgInop.

Abbreviated versions of the risk stratification strategy of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines have been recently validated in patients with pulmonary arterial hypertension. We aimed to investigate their prognostic value in medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients from the COMPERA registry, which collects six variables of interest (World Health Organization Functional Class, 6-min walk distance, brain natriuretic peptide, right atrial pressure, cardiac index and mixed venous oxygen saturation).We included patients with at least one follow-up visit, no pulmonary endarterectomy and at least three of the six variables available, and classified the patients into low-, intermediate- and high-risk groups. As a secondary analysis, the number of noninvasive low-risk criteria was counted. The association between risk assessment and survival was evaluated.Data from inclusion and follow-up (median 7 months) visits were available for 561 and 231 patients, respectively. Baseline 1- and 5-year survival estimates were significantly different (p<0.0001) in the baseline low-risk (98.6% and 88.3%, respectively), intermediate-risk (94.9% and 61.8%, respectively) and high-risk (75.5% and 32.9%, respectively) cohorts. Follow-up data were even more discriminative, with 100%, 92% and 69% 1-year survival, respectively. The number of low-risk noninvasive criteria was also associated with survival.These analyses suggest that the ESC/ERS risk assessment may be applicable in patients with medically treated CTEPH.

BACKGROUND Pulmonary hypertension (PH) is hemodynamically classified as pre-capillary (as seen in idiopathic pulmonary arterial hypertension [IPAH]) or post-capillary (as seen in heart failure with preserved ejection fraction [HFpEF]). Overlaps between these conditions exist. Some patients present with risk factors for left heart disease but precapillary PH, whereas patients with HFpEF may have combined preand post-capillary PH. OBJECTIVES This study sought to further characterize similarities and differences among patient populations with either PH-HFpEF or IPAH. METHODS We used registry data to analyze clinical characteristics, hemodynamics, and treatment responses in patients with typical IPAH (<3 risk factors for left heart disease; n 1⁄4 421), atypical IPAH ($3 risk factors for left heart disease; n 1⁄4 139), and PH-HFpEF (n 1⁄4 226) receiving PH-targeted therapy. RESULTS Compared with typical IPAH, patients with atypical IPAH and PH-HFpEF were older, had a higher body mass index, had more comorbidities, and had a lower 6-min walking distance, whereas mean pulmonary artery pressure (46.9 13.3 mm Hg vs. 43.9 10.7 mm Hg vs. 45.7 9.4 mm Hg, respectively) and cardiac index (2.3 0.8 l/min/m vs. 2.2 0.8 l/min/m vs. 2.2 0.7 l/min/m, respectively) were comparable among groups. After initiation of targeted PH therapies, all groups showed improvement in exercise capacity, functional class, and natriuretic peptides from baseline to 12 months, but treatment effects were less pronounced in patients with PH-HFpEF than typical IPAH; with atypical IPAH in between. Survival rates at 1, 3, and 5 years were almost identical for the 3 groups. CONCLUSIONS Patients with atypical IPAH share features of both typical IPAH and PH-HFpEF, suggesting that there may be a continuum between these conditions. (J Am Coll Cardiol 2016;68:368–78) © 2016 by the American College of Cardiology Foundation. Published by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). From the Department of Cardiology, DRK Kliniken Berlin, Berlin, Germany; Department of Cardiology, Medical University of Greifswald, Greifswald, Germany; Department of Respiratory Medicine and German Center of Lung Research (DZL), Hannover Medical School, Hannover, Germany; Department of Cardiology, National Heart & Lung Institute, Imperial College London, London, United Kingdom; Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center, München, Technical University Munich, Munich, Germany; Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, United Kingdom; Cardiology Department, Royal Free Hospital, London, United Kingdom; Division of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Department of Cardiology, Second University of Naples–Monaldi Hospital, Naples, Italy; Clinic of Pulmonology, University Hospital Zurich, Zurich, Switzerland; Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany; Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany; Centre for Pulmonary Hypertension, University Hospital, Heidelberg, Germany; Pulmonary Hypertension Unit Department of Cardiovascular and Respiratory Disease, University of Rome ‘La Sapienza,’ Rome, Italy; Medical Clinic I, Pneumology, Loewenstein Clinic, Loewenstein, Germany; Department of Internal Medicine, Unfallkrankenhaus Berlin, Berlin, Germany; Epidemiology Unit, German Rheumatism Research Centre, Berlin; Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany; Institute for Clinical Pharmacology, Medical Faculty, Technical University Carl Gustav Carus, Dresden, Germany; Clinic III for Internal Medicine (Cardiology), and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; and the Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany. COMPERA is currently supported by Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 8 , N O . 4 , 2 0 1 6 a 2 0 1 6 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U ND A T I O N . P U B L I S H E D B Y E L S E V I E R . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R T H E C C B Y N C N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y n c n d / 4 . 0 / ) . I S S N 0 7 3 5 1 0 9 7 h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 6 . 0 5 . 0 4 7

BACKGROUND:Riociguat was well tolerated and improved exercise and functional capacity in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) in a 12-week Phase II trial. We present final data from the long-term extension phase of this study. METHODS:During this multicenter, open-label, uncontrolled long-term extension study, riociguat dose could be changed at the physician's discretion (range 0.5-2.5 mg three times daily). The primary outcome was long-term safety and tolerability of riociguat; secondary outcomes included 6-minute walking distance, World Health Organization functional class, survival, and clinical worsening-free survival. RESULTS:Sixty-eight patients (inoperable CTEPH, n = 41; PAH, n = 27) entered the long-term extension. Median treatment duration at the final data cut-off was 77 months. The most common adverse events were nasopharyngitis (57%) and peripheral edema (37%). Three patients (4%) experienced serious adverse events of hemoptysis: two moderate, one severe, none fatal or considered drug-related. At Month 48, 6-minute walking distance increased from baseline by 69 ± 105 m, and World Health Organization functional class improved/stabilized/worsened versus baseline in 50/45/5% of patients. Three-year survival and clinical worsening-free survival were 91% and 49%, respectively (with patients censored if they withdrew without experiencing an event). Starting a new PAH treatment was the most frequent clinical worsening event. CONCLUSIONS:Improvements in exercise and functional capacity were maintained at 4 years in patients remaining on treatment, with no new safety signals identified. These data support riociguat as a long-term treatment option for PAH and inoperable CTEPH. TRIAL REGISTERED AT:ClinicalTrials.gov. REGISTRATION NUMBER:NCT00454558.

BACKGROUND Pulmonary hypertension (PH) is hemodynamically classified as pre-capillary (as seen in idiopathic pulmonary arterial hypertension [IPAH]) or post-capillary (as seen in heart failure with preserved ejection fraction [HFpEF]). Overlaps between these conditions exist. Some patients present with risk factors for left heart disease but precapillary PH, whereas patients with HFpEF may have combined pre- and post-capillary PH.OBJECTIVES This study sought to further characterize similarities and differences among patient populations with either PH-HFpEF or IPAH.METHODS We used registry data to analyze clinical characteristics, hemodynamics, and treatment responses in patients with typical IPAH (<3 risk factors for left heart disease; n = 421), atypical IPAH (>= 3 risk factors for left heart disease; n = 139), and PH-HFpEF (n = 226) receiving PH-targeted therapy.RESULTS Compared with typical IPAH, patients with atypical IPAH and PH-HFpEF were older, had a higher body mass index, had more comorbidities, and had a lower 6-min walking distance, whereas mean pulmonary artery pressure (46.9 +/- 13.3 mm Hg vs. 43.9 +/- 10.7 mm Hg vs. 45.7 +/- 9.4 mm Hg, respectively) and cardiac index (2.3 +/- 0.8 l/min/m(2) vs. 2.2 +/- 0.8 l/min/m(2) vs. 2.2 +/- 0.7 l/min/m(2), respectively) were comparable among groups. After initiation of targeted PH therapies, all groups showed improvement in exercise capacity, functional class, and natriuretic peptides from baseline to 12 months, but treatment effects were less pronounced in patients with PH-HFpEF than typical IPAH; with atypical IPAH in between. Survival rates at 1, 3, and 5 years were almost identical for the 3 groups.CONCLUSIONS Patients with atypical IPAH share features of both typical IPAH and PH-HFpEF, suggesting that there may be a continuum between these conditions. (C) 2016 by the American College of Cardiology Foundation. Published by Elsevier.

Riociguat is the first oral soluble guanylate cyclase stimulator shown to improve pulmonary hemodynamics in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH). This pilot study assessed the impact of a single dose of riociguat on hemodynamics, gas exchange, and lung function in patients with PH associated with chronic obstructive pulmonary disease (COPD). Adults with COPD-associated borderline or manifest PH (pulmonary vascular resistance > 270 dyn·s·cm(-5), mean pulmonary artery pressure ≥ 23 mmHg, ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity < 70%, and partial pressure of oxygen and carbon dioxide in arterial blood > 50 and ≤ 55 mmHg, respectively) received riociguat 1 or 2.5 mg during right heart catheterization. Twenty-two patients completed the study (11 men, 11 women, aged 56-82 years; 1-mg group: n = 10 [mean FEV1: 43.1%]; 2.5-mg group: n = 12 [mean FEV1: 41.2%]). Riociguat caused significant improvements (P < 0.01) from baseline in mean pulmonary artery pressure (1 mg: -3.60 mmHg [-11.44%]; 2.5 mg: -4.83 mmHg [-14.76%]) and pulmonary vascular resistance (1 mg: -58.32 dyn·s·cm(-5) [-15.35%]; 2.5 mg: -123.8 dyn·s·cm(-5) [-32.96%]). No relevant changes in lung function or gas exchange were observed. Single doses of riociguat were well tolerated and showed promising hemodynamic effects without untoward effects on gas exchange or lung function in patients with COPD-associated PH. Placebo-controlled studies of chronic treatment with riociguat are warranted.

Exercise training as an add-on to medical therapy has been shown to improve exercise capacity, quality of life, and possibly prognosis in patients with pulmonary hypertension (PH). The purpose of this study was to analyze the impact of exercise training on healthcare costs in PH.

Background-For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH).Methods and Results-We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH.Conclusions-The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH.

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival ( P =0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant ( P =0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01347216.