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Background: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes., Methods: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured., Results: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival., Conclusions: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response., Competing Interests: Disclosures Dr Gerhardt reports remuneration for lectures from Actelion, Bayer, Janssen, and MSD, and grants to the institution from Actelion, Bayer, and Janssen. E. Fiessler reports no disclosures. Dr Olsson reports fees for lectures or consultations from Acceleron, Actelion, Bayer, Janssen, United Therapeutics, MSD, GSK, and Pfizer. Dr Kayser reports no disclosures. Dr Kovacs reports personal fees for lectures or consultancy from Actelion, Bayer, GSK, MSD, Novartis, Pfizer, Chiesi, and Boehringer-Ingelheim. Dr Gall reports fees for lectures or consultancy from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Ghofrani reports personal fees and consultancy fees from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer; other from Bellerophon Pulse Technologies; and consultancy fees from MSD. Dr Eslam reports no disclosures. Dr Lang reports remuneration for lectures or consultancy from Actelion, AOP Orphan, AstraZeneca, Bayer-Schering, Cordis, Daiichi-Sankyo, Ferrer, Neutrolis, Janssen, and United Therapeutics. N. Benjamin reports fees for lectures from Actelion, Bayer, MSD, and Janssen. Dr Grünig reports fees for lectures or consultations from Actelion, Bayer, GSK, Janssen, MSD, Pfizer, and United Therapeutics. Dr Halank reports remuneration for consultancy or lectures from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GSK, Janssen, MSD, and Novartis. Dr Lange reports personal fees for lectures or consultancy from Acceleron Pharma, Actelion, Bayer, GSK, Janssen-Cilag, MSD, Pfizer, and United Therapeutics; and grants to the institution from Acceleron Pharma, Actelion, Bayer, Bellerophon, Gilead, Janssen-Cilag, Pfizer, and United Therapeutics. Dr Ulrich reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss; and grants and personal fees from Actelion, Johnson & Johnson, and MSD. Dr Leuchte reports fees for lectures or consultancy from Actelion, Bayer, GSK, Merck, and Pfizer. Dr Held reports personal fees for lectures or consultancy from Actelion, AstraZeneca, Bayer, Berlin Chemie, Boehringer, GSK, Janssen, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Klose reports speaker or consultancy fees from Actelion, Bayer, Berlin Chemie, GSK, MSD, Novartis, Pfizer, and United Therapeutics. Dr Ewert reports lecture fees from Actelion, AstraZeneca, Bayer, and OMT; and industry-sponsored grants from Actelion and OMT. Dr Wilkens reports personal fees from Actelion, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche. Dr Pizarro reports honoraria for lectures from Actelion and Janssen. Dr Skowasch reports honoraria for lectures and consultancy from Actelion and Janssen. Dr Wissmüller reports remunerations for lectures from Janssen. Dr Hellmich reports no disclosures. Dr Olschewski reports remuneration for lectures or consultancy or grants to the institution from Actelion, Bayer, Belerophon, Boehringer, GSK, Inventiva, Janssen, Menarini, MSD, Novartis, Pfizer, and Roche. Dr Hoeper reports fees for consultations or lectures from Acceleron, Actelion, Bayer, Janssen, MSD, and Pfizer. Dr Rosenkranz reports remuneration for lectures or consultancy from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, OMT, Pfizer, United Therapeutics, and Vifor; and grants to the institution from Actelion, AstraZeneca, Bayer, and Janssen.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Within the last decade, the age at diagnosis of patients with pulmonary arterial hypertension has increased, which led to a change of the clinical phenoype being associated with more comorbidities. Cluster analyses of registry data have identified cardiac, cardio-pulmonary and classical phenotypes of pulmonary arterial hypertension.Subgroup analyses of randomised controlled trials and registry data indicate, that in patients with pulmonary arterial hypertension and cardiac comorbidities, especially the left-heart phenotype, a closely supervised combination treatment may be considered. The 4-strata model may be used for monitoring and risk stratification in these patients. Individual treatment decisions should be made in the pulmonary hypertension centre. Factors such as hemodynamics, age, phenotype, number and severity of comorbidities, therapy response, adverse reactions and the wish of the patient should be considered.Prospective, randomized studies to assess the efficacy and safety profile of pulmonary arterial hypertension treatments are desirable. Patients with a mainly pulmonary phenotype (smoking, diffusion capacity of the lung < 45 % and/or lung parenchymal changes) may have less benefit of oral medication., Competing Interests: E.G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.M.H. hat Honorare für Vorträge/Konsultationen von AstraZeneca, Janssen und MSD erhalten.C.N. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GSK, Janssen und OMT erhalten.J.B. erhielt Honorare für Vorträge und Beratertätigkeit von Astra-Zeneca, Biogen, Boehringer-Ingelheim, BMS, Ferrer, Novartis, Roche und Sanofi-Genzyme. Für Tätigkeiten im Rahmen von Data Monitoring and Safety Boards erhielt er Honorare von Actelion und Galapagos. Es besteht kein Zusammenhang mit der vorliegenden Publikation.K.M.K. hat Vortrags- und/oder Beratungshonorare erhalten von AOP, AstraZeneca, Chiesi, GSK, Janssen, MSD, Novartis, Sanofi.J.R. hat keinen Interessenkonflikt.M.L.: Unterstützung zur Teilnahme an medizinischen Kongressen/Fort- und Weiterbildungen von MSD, Orpha Swiss, Janssen. Advisory-Board-Tätigkeiten für MSD (bezahlt) und Orpha Swiss (unbezahlt).N.B. erhielt Vortragshonorare des Universitätsspitals Zürich für Vortragstätigkeiten.T.J.L. hat Honorare für Vorträge und/oder Beratungstätigkeit und/oder Unterstützung für die Teilnahme an Fortbildungen erhalten von Acceleron Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Ferrer, Gossamer Bio, Janssen Cilag, MSD, Orphacare und Pfizer.S.U. hat Forschungsgelder des Schweizerischen Nationalfond, der Zürcher und Schweizer Lungenliga, der EMDO-Foundation, zudem Forschungsgelder und Unterstützung für Vorträge, Reisen und Beratungshonorare von Janssen SA, Orpha Swiss, MSD und Novartis erhalten, alle nicht im Zusammenhang mit dieser Arbeit.H.W.: Referenten- und/oder Beratertätigkeit für Bayer AG, Biotest, Boehringer Ingelheim, Daiichi Sanchyo, Ferrer, GSK, Janssen, MSD und Roche.C.G.: Advisory Board Treffen: Pfizer, Janssen, Bayer.D.S.: Vortrags- und Beratungshonorare und/oder Forschungsunterstützung von AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, DFG, BMBF., (Thieme. All rights reserved.)

2022, the updated guidelines for the diagnosis and treatment of pulmonary hypertension (PH) of the European Societies of Cardiology and Pneumology were published. This resulted in important innovations concerning the hemodynamic definition as well as diagnosis and therapy of PH. In the following, an overview of the definition and classification of PH will be given, followed by a discussion of risk stratification and therapy of pulmonary arterial hypertension (PAH)., Competing Interests: Dirk Skowasch: Vortrags- und Beratungshonorare von Janssen, MSD., (Thieme. All rights reserved.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Guideline recommendations highlight the critical role of combination therapy for the treatment of pulmonary arterial hypertension (PAH). Conversely, registry data demonstrate that a considerable number of PAH patients remain on monotherapy. The reasons for this discrepancy remain elusive. The aim of this study was to assess the patient profiles, treatment patterns, and disease characteristics of patients diagnosed with PAH who were kept on monotherapy at experienced pulmonary hypertension (PH) centres and to capture potential reasons for monotherapy., Methods and Results: We analysed the patient profiles of 182 patients on monotherapy with PAH-targeted drugs, managed at experienced PH expert centres (Cologne, Giessen, Heidelberg, and Dresden). Patients were identified based on their latest follow-up visit and analysed retrospectively from the time of PAH diagnosis to last follow-up. Patients were dichotomized by age, and patient characteristics, treatment patterns, response to therapy, change in risk status, and drug tolerability were recorded during the course of their disease. Patients' mean age was 69.1 ± 13.1 years at the most recent follow-up (Key Time Point 1) and 64.5 ± 14.9 years at the time of diagnosis (Key Time Point 2). The mean time on monotherapy was 60.7 ± 53.8 months; 35.7/64.3% of patients were male/female. The majority (66.5%) had idiopathic PAH, followed by PAH associated with connective tissue disease (17.0%) and portopulmonary PH (8.2%). Among patients on monotherapy, there were five main clusters: (i) patients with failed escalation attempts mostly because of intolerability (26.9%); (ii) low risk on monotherapy, favourable response, and no reason for escalation (24.2%); (iii) patients with mild PAH (36.3%); (iv) elderly patients with PAH and multiple co-morbidities (38.5%); and (v) patients with associated forms of PAH where the level of evidence for combination therapies is considered low (16.5%). There were substantial differences between patients above or below the median age (68 years). The most frequently used monotherapy for PAH was phosphodiesterase type 5 inhibitors (75.3%)., Conclusions: A considerable number of PAH patients are on monotherapy at large PH expert centres, characterized by specific reasons that justify this kind of treatment. Nevertheless, as comprehensive treatment strategies have shown improved long-term outcomes even in mildly symptomatic patients, each case of monotherapy should be justified., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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., Competing Interests: Conflict of interest: M.M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer. Conflict of interest: C. Pausch has nothing to disclose. Conflict of interest: K.M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: D. Huscher has received travel compensation from Shire. Conflict of interest: D. Pittrow has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Sanofi-Genzyme, Takeda and Viatris. Conflict of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: G. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer, GSK, Novartis and Pfizer. Conflict of interest: C.D. Vizza has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: H. Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. Conflict of interest: O. Distler has/had consultancy relationship and/or has received research funding from 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GSK, Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm and Sinoxa in the area of potential treatments of scleroderma and its complications including PAH; and has a patent mir-29 for the treatment of systemic sclerosis licensed. Conflict of interest: C. Opitz has nothing to disclose. Conflict of interest: J.S.R. Gibbs has received fees for lectures and/or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: M. Delcroix reports research grants from Actelion/J&J, speaker and consultant fees from Bayer, MSD, Acceleron, AOP and Daiichi Sankyo, outside the submitted work; and is holder of the Janssen Chair for Pulmonary Hypertension at the KU Leuven. Conflict of interest: H.A. Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly and Novartis; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive and Ergonex; has received governmental grants from the German Research Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE) and the German Ministry for Education and Research (BMBF). Conflict of interest: D-H. Park has nothing to disclose. Conflict of interest: R. Ewert has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen, Lilly, MSD, Novartis, Pfizer and United Therapeutics. Conflict of interest: H. Kaemmerer has received honoraria for lectures and/or consultancy from Actelion, Bristol Myers Squibb and Janssen. Conflict of interest: H-J. Kabitz has received fees from Löwenstein Medical, Weinmann, Philips Respironics, ResMed, Vivisol, Sapio Life and Sanofi-Genzyme. Conflict of interest: D. Skowasch received fees for lectures and/or consulting and/or research support (paid to institution) from Actelion, Bayer, GSK, Janssen, MSD and Pfizer. Conflict of interest: J. Behr received grants from Actelion, Bayer, Biogen, Boehringer Ingelheim, Galapagos, Novartis, Roche and Sanofi/Genzyme. Conflict of interest: K. Milger has received fees from Actelion, AstraZeneca, GSK, Janssen, MSD, Novartis and Sanofi-Aventis. Conflict of interest: M. Halank has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GSK, Janssen and Novartis. Conflict of interest: H. Wilkens received fees for lectures and/or consultations from Actelion, Bayer, Biotest, Boehringer, GSK, Janssen, Pfizer and Roche. Conflict of interest: H-J. Seyfarth has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen and MSD. Conflict of interest: M. Held has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. Conflict of interest: D. Dumitrescu declares honoraria for lectures and/or consultancy from Actelion, AstraZeneca, Bayer, GSK, Janssen, MSD, Novartis, Pfizer, Servier and Vifor. Conflict of interest: I. Tsangaris has received fees from Actelion, Bayer, ELPEN, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: A. Vonk-Noordegraaf reports receiving fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflict of interest: S. Ulrich reports personal fees from Actelion, Janssen and MSD outside the submitted work. Conflict of interest: H. Klose has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen, MSD, Novartis, Pfizer and United Therapeutics. Conflict of interest: M. Claussen reports honoraria for lectures from Boehringer Ingelheim Pharma GmbH and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. Conflict of interest: T.J. Lange has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GSK, Janssen-Cilag, MSD, Pfizer and United Therapeutics. Conflict of interest: S. Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Bayer, BMS, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor; research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis., (Copyright ©The authors 2022.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Since 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival., Methods: We analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010-2014 and 2015-2019., Results: A total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010-2014 and 2015-2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2-90.9%) and 90.8% (95% CI 89.3-92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0-70.8%) and 70.5% (95% CI 67.8-73.4%), respectively)., Conclusions: The use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed., Competing Interests: Conflicts of interest: M.M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflicts of interest: C. Pausch has no disclosures. Conflicts of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: G. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer, GlaxoSmithKline, Novartis and Pfizer. Conflicts of interest: D. Huscher has received consulting fees from Actelion. Conflicts of interest: D. Pittrow has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Takeda and Viatris. Conflicts of interest: K.M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: C.D. Vizza has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: H. Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. Conflicts of interest: O. Distler has/had consultancy relationship and/or has received research funding from 4D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, EspeRare Foundation, GlaxoSmithKline, Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm and Sinoxa, in the area of potential treatments of scleroderma and its complications including PAH; in addition, the author has a patent “mir-29 for the treatment of systemic sclerosis” licensed. Conflicts of interest: C. Opitz has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer. Conflicts of interest: J.S.R. Gibbs has received fees for lectures and/or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: M. Delcroix reports research grants from Actelion/J&J, speaker and consultant fees from Bayer, MSD, Acceleron, AOP and Daiichi Sankyo, outside the submitted work; and is holder of the Janssen Chair for Pulmonary Hypertension at the KU Leuven. Conflicts of interest: H.A. Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly and Novartis; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GlaxoSmithKline, Actelion, Lilly, Merck, Encysive and Ergonex; and has also received governmental grants from the German Research Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE) and the German Ministry for Education and Research (BMBF). Conflicts of interest: S. Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Bayer, BMS, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor; research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis. Conflicts of interest: D-H. Park has nothing to disclose. Conflicts of interest: R. Ewert has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer and United Therapeutics. Conflicts of interest: H. Kaemmerer has received honoraria for lectures and/or consultancy from Actelion, BMS and Janssen. Conflicts of interest: T.J. Lange has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, MSD, Pfizer and United Therapeutics. Conflicts of interest: H-J. Kabitz has received fees from Löwenstein Medical, Weinmann, Philips Respironics, ResMed, Vivisol, Sapio Life and Sanofi-Genzyme. Conflicts of interest: D. Skowasch received fees for lectures and/or consulting and/or research support to institution from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflicts of interest: A. Skride reports no conflicts of interest. Conflicts of interest: M. Claussen reports honoraria for lectures from Boehringer Ingelheim Pharma GmbH and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. Conflicts of interest: J. Behr received grants from Actelion, Bayer, Biogen, Boehringer Ingelheim, Galapagos, Novartis, Roche and Sanofi/Genzyme. Conflicts of interest: K. Milger has received fees from Actelion, AstraZeneca, GlaxoSmithKline, Janssen, MSD, Novartis and Sanofi-Aventis. Conflicts of interest: M. Halank has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GlaxoSmithKline, Janssen and Novartis. Conflicts of interest: H. Wilkens received personal fees from Actelion, Bayer, Biotest, Boehringer, GlaxoSmithKline, Janssen, Pfizer and Roche. Conflicts of interest: H-J. Seyfarth has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen and MSD. Conflicts of interest: M. Held has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. Conflicts of interest: D. Dumitrescu declares honoraria for lectures and/or consultancy from Actelion, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer and Servier. Conflicts of interest: I. Tsangaris has received fees from Actelion, Bayer, ELPEN, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: A. Vonk-Noordegraaf reports receiving fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflicts of interest: S. Ulrich reports personal fees from Actelion, Janssen and MSD outside the submitted work. Conflicts of interest: H. Klose has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer and United Therapeutics., (Copyright ©The authors 2022.)